(The Conversation is an independent and nonprofit source of news, analysis and commentary from academic experts.)

Craig W. Stevens, Oklahoma State University

(THE CONVERSATION) Even as the COVID-19 pandemic cripples the economy and kills hundreds of people each day, there is another epidemic that continues to kill tens of thousands of people each year through opioid drug overdose.

Opioid analgesic drugs, like morphine and oxycodone, are the classic double-edged swords. They are the very best drugs to stop severe pain but also the class of drugs most likely to kill the person taking them. In a recent journal article, I outlined how a combination of state-of-the-art molecular techniques, such as CRISPR gene editing and brain microinjection methods, could be used to blunt one edge of the sword and make opioid drugs safer.

I am a pharmacologist interested in the way opioid drugs such as morphine and fentanyl can blunt pain. I became fascinated in biology at the time when endorphins natural opioids made by our bodies were discovered. I have been intrigued by the way opioid drugs work and their targets in the brain, the opioid receptors, for the last 30 years. In my paper, I propose a way to prevent opioid overdoses by modifying an opioid users brain cells using advanced technology.

Opioid receptors stop breathing

Opioids kill by stopping a person from breathing (respiratory depression). They do so by acting on a specific set of respiratory nerves, or neurons, found in the lower part of the brain that contain opioid receptors. Opioid receptors are proteins that bind morphine, heroin and other opioid drugs. The binding of an opioid to its receptor triggers a reaction in neurons that reduces their activity. Opioid receptors on pain neurons mediate the pain-killing, or analgesic, effects of opioids. When opioids bind to opioid receptors on respiratory neurons, they slow breathing or, in the case of an opioid overdose, stop it entirely.

Respiratory neurons are located in the brainstem, the tail-end part of the brain that continues into the spine as the spinal cord. Animal studies show that opioid receptors on respiratory neurons are responsible for opioid-induced respiratory depression the cause of opioid overdose. Genetically altered mice born without opioid receptors do not die from large doses of morphine unlike mice with these receptors present.

Unlike laboratory mice, humans cannot be altered when embryos to remove all opioid receptors from the brain and elsewhere. Nor would it be a good idea. Humans need opioid receptors to serve as the targets for our natural opioid substances, the endorphins, which are released into the brain during times of high stress and pain.

Also, a total opioid receptor knockout in humans would leave that person unresponsive to the beneficial pain-killing effects of opioids. In my journal article, I argue that what is needed is a selective receptor removal of the opioid receptors on respiratory neurons. Having reviewed the available technology, I believe this can be done by combining CRISPR gene editing and a new neurosurgical microinjection technique.

CRISPR to the rescue: Destroying opioid receptors

CRISPR, which is an acronym for clustered regularly interspaced short palindromic repeats, is a gene editing method that was discovered in the genome of bacteria. Bacteria get infected by viruses too and CRISPR is a strategy that bacteria evolved to cut-up the viral genes and kill invading pathogens.

The CRISPR method allows researchers to target specific genes expressed in cell lines, tissues, or whole organisms, to be cut-up and removed knocked out or otherwise altered. There is a commercially available CRISPR kit which knocks out human opioid receptors produced in cells that are grown in cell cultures in the lab. While this CRISPR kit is formulated for in vitro use, similar conditional opioid receptor knock-out techniques have been demonstrated in live mice.

To knockout opioid receptors in human respiratory neurons, a sterile solution containing CRISPR gene-editing molecules would be prepared in the laboratory. Besides the gene-editing components, the solution contains chemical reagents that allow the gene-editing machinery to enter the respiratory neurons and make their way into the nucleus and into the neurons genome.

How does one get the CRISPR opioid receptor knockout solution into a persons respiratory neurons?

Enter the intracranial microinjection instrument (IMI) developed by Miles Cunningham and his colleagues at Harvard. The IMI allows for computer-controlled delivery of small volumes of solution at specific places in the brain by using an extremely thin tube about twice the diameter of a human hair that can enter the brain at the base of the skull and thread through brain tissue without damage.

The computer can direct the robotic placement of the tube as it is fed images of the brain taken before the procedure using MRI. But even better, the IMI also has a recording wire embedded in the tube that allows measurement of neuronal activity to identify the right group of nerve cells.

Because the brain itself feels no pain, the procedure could be done in a conscious patient using only local anesthetics to numb the skin. Respiratory neurons drive the breathing muscles by firing action potentials which are measured by the recording wire in the tube. When the activity of the respiratory neurons matches the breathing movements by the patients, the proper location of the tube is confirmed and the CRISPR solution injected.

The call for drastic action

Opioid receptors on neurons in the brain have a half-life of about 45 minutes. Over a period of several hours, the opioid receptors on respiratory neurons would degrade and the CRISPR gene-editing machinery embedded in the genome would prevent new opioid receptors from appearing. If this works, the patient would be protected from opioid overdose within 24 hours. Because the respiratory neurons do not replenish, the CRISPR opioid receptor knockout should last for life.

With no opioid receptors on respiratory neurons, the opioid user cannot die from opioid overdose. After proper backing from National Institute on Drug Abuse and leading research and health care institutions, I believe CRISPR treatment could enter clinical trials in between five to 10 years. The total cost of opioid-involved overdose deaths is about US$430 billion per year. CRISPR treatment of only 10% of high-risk opioid users in one year would save thousands of lives and $43 billion.

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Intracranial microinjection of CRISPR solutions might seem drastic. But drastic actions that are needed to save human lives from opioid overdoses. A large segment of the opioid overdose victims are chronic pain patients. It may be possible that chronic pain patients in a terminal phase of their lives and in hospice care would volunteer in phase I clinical trials for the CRISPR opioid receptor knockout treatment I propose here.

Making the opioid user impervious to death by opioids is a permanent solution to a horrendous problem that has resisted efforts by prevention, treatment and pharmacological means. Steady and well-funded work to prove the CRISPR method, first with preclinical animal models then in clinical trials, is a moonshot for the present generation of biomedical scientists.

This article is republished from The Conversation under a Creative Commons license. Read the original article here: https://theconversation.com/how-gene-editing-a-persons-brain-cells-could-be-used-to-curb-the-opioid-epidemic-143165.

Excerpt from:
How gene editing a person's brain cells could be used to curb the opioid epidemic - Huron Daily Tribune

Recommendation and review posted by Bethany Smith

Dublin, Aug. 04, 2020 (GLOBE NEWSWIRE) -- The "CRISPR Technology Global Market Report 2020-30: COVID-19 Growth and Change" report has been added to ResearchAndMarkets.com's offering.

Where is the largest and fastest growing market for the crispr technology market? How does the market relate to the overall economy, demography and other similar markets? What forces will shape the market going forward? This global market report answers all these questions and many more.

The global CRISPR technology market is expected to increase from $0.76 billion in 2019 to $0.92 billion in 2020 at a compound annual growth rate (CAGR) of 20.91%. The exponential growth is mainly due to the COVID-19 outbreak that has led to the research for drugs for COVID-19 with gene-editing using CRISPR technology. The market is expected to reach $1.55 billion in 2023 at a CAGR of 19.13%.

The application of CRISPR technology as a diagnostic tool is expected to boost the market during the period. The Sherlock CRISPR SARS-CoV-2 kit is the first diagnostic kit based on CRISPR technology for infectious diseases caused due to COVID-19. In May 2020, FDA announced the emergency use authorization to the Sherlock BioSciences Inc's Sherlock CRISPR SARS-CoV-2 kit which is a CRISPR-based SHERLOCK (Specific High-sensitivity Enzymatic Reporter unLOCKing) diagnostic test. This test helps in specifically targeting RNA or DNA sequences of the SARS-CoV-2 virus from specimens or samples such as nasal swabs from the upper respiratory tract and fluid in the lungs from bronchoalveolar lavage specimens. This diagnostic kit has high specificity and sensitivity and does not provide false negative or positive results. Widening the application of CRISPR technology for the diagnosis of infectious diseases will increase the demand for CRISPR technology products and services.

North America was the largest region in the CRISPR technology market in 2019. Europe was the second-largest region in the CRISPR technology market in 2019.

Stringent government regulations are expected to retard the growth of the CRISPR technology market during the period. Several advancements in CRISPR technology are trending in the market during the period.

Major players in the CRISPR technology market are Thermo Fisher Scientific, GenScript Biotech Corporation, CRISPR Therapeutics AG, Editas Medicine, Horizon Discovery plc, Integrated DNA Technologies, Inc. (Danaher), Origene Technologies, Inc., Transposagenbio Biopharmaceuticals (Hera Biolabs), Intellia Therapeutics Inc., and GeneCopoeia, Inc.

Report ScopeThe report covers market characteristics, size and growth, segmentation, regional and country breakdowns, competitive landscape, market shares, trends and strategies for this market. It traces the market's historic and forecast market growth by geography. It places the market within the context of the wider crispr technology market, and compares it with other markets.

Companies Mentioned (A-Z)

For more information about this report visit https://www.researchandmarkets.com/r/8msd9m

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Read the original:
CRISPR Technology Market to Grow by 20.91% in 2020, Accelerated by the Outbreak of COVID-19 - Industry Projections to 2030 - Yahoo Finance

Recommendation and review posted by Bethany Smith

Organ Transplant Rejection Medications Market: Introduction

According to the report, the globalorgan transplant rejection medications marketwas valued atUS$ 4.7 Bn in 2018and is projected to expand at a CAGR of~3% from 2019 to 2027. Rise in healthcare spending and improvements in healthcare infrastructure, and increase in the global geriatric population are the major factors anticipated to drive the organ transplant rejection Medication market from2019 to 2027.

Rise in Healthcare Spending and Improvement in Healthcare Infrastructure to Drive Global Market

Increase in patient awareness about personal health boosts the demand for medical devices. Patients are more aware and proactive about their health and are willing to seek a physician's advice at an early stage. Increase in per capita disposable income is encouraging people to spend more on healthcare facilities, which, in turn, fuels the global organ transplant rejection medications market. Advertisements have increased public visibility of new technology, thereby generating interest among chronic patients for organ transplant rejection medications.

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Changing demographics in emerging economies such as China, India, Brazil, and South Africa are expected to provide significant opportunities for organ transplant rejection medications. Moreover, public and private healthcare expenditure is expected to increase in these countries, which is likely to drive the organ transplant rejection medications market.

Increase in healthcare expenditure, rise in global per capita income, and improvement in healthcare infrastructure and government reimbursement programs in developed as well as developing countries are likely to propel the organ transplant rejection medications market in the near future.

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Kidney Transplant to Offer Lucrative Opportunities

The report offers detailed segmentation of the global organ transplant rejection medications market based on drug class, transplant type, distribution channel, and region. In terms of drug class, the organ transplant rejection medications market has been segmented into calcineurin inhibitors, antiproliferative agents, mTOR inhibitors, antibodies, and steroids. Based on transplant type, the market has been segmented into kidney transplant, bone marrow transplant, liver transplant, heart transplant, lung transplant, and other transplants. Kidney transplant is a highly preferred treatment for end-stage renal disease (ESRD). It is comparatively more cost-effective than dialysis and is associated with a long-term mortality improvement.

Based on distribution channel, the global organ transplant rejection medications market has been classified into hospital pharmacies, retail pharmacies, and online pharmacies. Hospitals are major clinical settings wherein a large number of surgeries are conducted. This makes hospital pharmacies a prominent segment of the organ transplant rejection medications market.

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North America to Lead Organ Transplant Rejection Medications Market

North America was the largest market for organ transplant rejection medications in 2018, due to presence of the maximum number of living as well as deceased donors and better organ-preserving practices in the region. However, high costs and complex procedures would adversely affect the organ transplant rejection medications market during the forecast period. The organ transplant rejection medications market in Asia Pacific is projected to expand at a relatively high CAGR of4.1%during the forecast period. Transplantation procedures vary substantially from region to region and country to country, due to factors such as difference in the rate of end-organ damage, economic differences in terms of ability to provide transplants or other treatments, cultural differences that can support or hinder organ donation and transplant, and reporting of legal transplants across regions.

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Major Market Players

The report provides profiles of leading players operating in the global organ transplant rejection medications market. These includeGlaxoSmithKline plc, Novartis AG, F. Hoffmann-La Roche Ltd., Astellas Pharma, Inc., Pfizer, Inc., AbbVie, Inc., Allergan plc, Bristol-Myers Squibb Company (BMS), and Sanofi.

Novartis AG is a leading company that specializes in the development and manufacture of branded as well as generic pharmaceutical and biopharmaceutical drugs. It is evaluating the experimental Facilitating Cell Therapy (FCR001), which involves taking stem cells of a kidney donor and grafting them in the transplant recipients bone marrow. This combination would trick the recipients immune system by accepting the donated kidney as its own.

Pfizer, Inc. is a global pharmaceutical company that develops, manufactures, and markets prescription medicines in 11 therapeutic segments, including cardiovascular, oncology, neuroscience, pain, and infectious diseases. The company offers a range of medicines and vaccines as well as consumer healthcare products for the prevention and treatment of infectious and chronic diseases for all age groups.

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Organ Transplant Rejection Medications Market: Drug Companies Focus on Improving Long-term Outcome of New Drugs - BioSpace

Recommendation and review posted by Bethany Smith

Sketch pencil in her right hand, Laida Arcia Carro (pictured above) adds tiny details to complete her portrait of a strong Haitian woman. Ms. Carro cant imagine a day without drawing, yet at age 71 the osteoarthritis in her hands often forces her to end her sketch sessions sooner than shed like.

Four or five years ago I noticed that my graspwasnt as good as it had been, and I had pain with certain motions, likeopening a jar, said Ms. Carro, a retired elementary school art teacher. Itgot progressively worse and now the bone on the inner side of my wristprotrudes. Its in both hands, but my right is worse than my left.

Unfortunately, just being female places Ms. Carro at a higher risk for a hand or wrist problem. According to the National Institutes of Health, women are about three times more likely than men to suffer from rheumatoid arthritis and carpal tunnel syndrome, and twice as likely to fracture a wrist or have osteoarthritis in their hands. The gender gap is true across all age groups, yet it widens as we age.

Genetics, hormones, anatomy and metabolism all play arole, said Elizabeth Anne Ouellette, M.D., chief of hand surgery at Miami Orthopedics & Sports MedicineInstitute. Inaddition, women often lack adequate levels of calcium and vitamin D, importantin forming and maintaining strong bones.

Although Dr. Ouellette is an orthopedic surgeon, sheisnt quick to take a patient to the operating room. Im going to talk you outof surgery if I can, she said. If you arent sleeping because of the pain oryour life is severely disrupted for example, you cant turn the key in yourfront door then we have a conversation about surgery.

Dr. Ouellette understands what her patients areexperiencing because early in her career, just after having her second child,she underwent carpal tunnel surgery on both wrists at the same time. I wasbeginning to lose finger sensation and I was not sleeping. This could havebrought an end to my career.

Because of the impact a hand problem may have on dailylife, its important to see a specialist if you have symptoms. The hand andwrist are delicate and complex, with 27 bones and many muscles, tendons,ligaments, arteries, veins and nerves. Many conditions can be addressed, andtechnology is constantly evolving to improve and expand treatment. Dr.Ouellette is involved in a wide range of research on everything from nerveinjuries to the use of tiny anchors in the wrist for tendon repairs. Inaddition to her role at Baptist Health, she is chief of hand surgery and aclinical professor of orthopedics at Florida International Universitys HerbertWertheim College of Medicine.

Although Ms. Carro is a candidate for surgery, she andDr. Ouellette discussed the options, and together, they decided to watch and wait.Her symptoms could improve with conservative treatment, Dr. Ouellette said.And sometimes patients have no pain after the cartilage has worn down and thejoint is bone on bone. Then we do nothing. Waiting could also mean thatmedical developments, such as tissue re-engineering, could move from theresearch setting to everyday use.

Occasionally, Ms. Carro wears asplint on her hand, takes anti-inflammatory medicines and rubs on a topicalnumbing cream. She hopes to avoid the disruption surgery would require. Whenshe can, she still teaches private art lessons and attends regular drawingclasses, and hopes those resume soon. Careful to maintain social distancingduring the pandemic, Ms. Carro has filled her days by continuing her sketching,except without live models.

My art is so important, she said.I dont want to stop. It keeps me alive.

Tips for handling the future:

Dr. Ouellette has 30 years of experience in researchand in treating athletes and people of all ages who need small jointreplacement or surgery for hand, wrist and joint injuries. She offers patientsplenty of advice when it comes to preventing or slowing problems that canbecome debilitating.

Some suggestions:

MAINTAIN A HEALTHY WEIGHT. Fat contributes to a higher level of the hormoneleptin, which leads to inflammation. Its not the extra weight on joints thatcauses problems, she explained. Inflammation can cause swelling, cartilageand bone damage, and pain. Leptin has been linked to arthritis, lupus,multiple sclerosis and even heart disease.

EXERCISE. It keeps bones strong, improves balance, buildsmuscle and has long-lasting health benefits for the whole body.

FEED YOUR BONES. Take a vitamin D supplement and eat plenty ofdark green, leafy vegetables to increase your calcium level.

CHOOSE ORGANIC. The fewer chemicals youabsorb from skin care products, makeup and food, the better. Apps such as EWGHealthy Living, Think Dirty and Detox Me can help you determine your toxicityexposure.

Tags: carpal tunnel syndrome, Miami Orthopedics & Sports Medicine Institute

Excerpt from:
Helping Hands: Expert Care can Help with Hand Conditions - Baptist Health South Florida

Recommendation and review posted by Bethany Smith

ROSELAND, N.J., Aug. 04, 2020 (GLOBE NEWSWIRE) -- RenovaCare, Inc. (Symbol: RCAR; http://www.renovacareinc.com), developer of patented technologies for spraying self-donated stem cells for the regeneration of skin and other organs and tissues, today announced the appointment of Lydia M. Evans, M.D. to its Board of Directors. A noted dermatologist, oncologist, and doctor of internal medicine, Dr. Evans has held numerous academic, private, and commercial appointments, and brings extensive insights into the science, technology, and market positioning of wound and skin regeneration therapies.

As RenovaCare continues to advance our portfolio of regenerative technologies, strategic leadership from our Board is increasingly critical as we look to regulatory approval and commercialization. Dr. Evans’ knowledge and experience will be a strong addition to our Board at such an important time as the Company continues to pursue bringing first-in-class regenerative therapies to market,” stated Alan L. Rubino, RenovaCare CEO & President.

"I’m pleased to join the RenovaCare Board of Directors at a time of growing demand for modern therapies that promise natural regeneration for burns, wounds, skin disorders and cosmetic imperfections. The RenovaCare CellMist and SkinGun represent an impressive therapeutic approach that replaces painful and complex skin grafting procedures with a gentle mist of the patient’s own cells. I look forward to assisting the Company in its development,” concluded Dr. Evans.

A Columbia Presbyterian and Memorial Sloan Kettering-educated dermatologist, oncologist and doctor of internal medicine, Dr. Evans specializes in state-of-the-art treatments for aesthetic and medical dermatologic procedures. She is currently an Associate Clinical Attending Physician in the Department of Dermatology at New York Presbyterian Medical Center in New York City, a position which includes significant teaching responsibilities. She is also a Fellow of the American Academy of Dermatology, a Diplomate of the National Board of Medical Examiners, the American Board of Internal Medicine, and the American Board of Dermatology. She is a member of the Leadership Society of the Dermatology Research Foundation and has served as the New York State Chairperson for the Psoriasis Research Foundation. Dr. Evans was Consulting Dermatologist to L’Oral Paris from 2000 to 2012, spurring new product development in dermatologist-inspired skincare directly to consumers. About RenovaCare RenovaCare, Inc. is developing first-of-its-kind autologous (self-donated) stem cell therapies for the regeneration of human organs. Its initial product under development targets the body’s largest organ, the skin. The company’s flagship technology, the CellMist System, uses its patented SkinGun to spray a liquid suspension of a patient’s stem cells the CellMist Solution onto wounds.

RenovaCare is developing its CellMist System as a promising new alternative for patients suffering from burns, chronic and acute wounds, and scars. In the US alone, this $45 billion market is greater than the spending on high-blood pressure management, cholesterol treatments, and back pain therapeutics.

RenovaCare products are currently in development. They are not available for sale in the United States. There is no assurance that the Company’s planned or filed submissions to the U.S. Food and Drug Administration will be accepted or cleared by the FDA.

For additional information, please call Amit Singh at: 888-398-0202 or visit: https://renovacareinc.com

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Social Media Disclaimer Investors and others should note that we announce material financial information to our investors using SEC filings and press releases. We use our website and social media to communicate with our subscribers, shareholders and the public about the company, RenovaCare, Inc. development, and other corporate matters that are in the public domain. At this time, the company will not post information on social media that could be deemed to be material information unless that information was distributed to public distribution channels first.

We encourage investors, the media, and others interested in the company to review the information we post on the company’s website and the social media channels listed below:

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Legal Notice Regarding Forward-Looking Statements No statement herein should be considered an offer or a solicitation of an offer for the purchase or sale of any securities. This release contains forward-looking statements that are based upon current expectations or beliefs, as well as a number of assumptions about future events. Although RenovaCare, Inc. (the Company”) believes that the expectations reflected in the forward-looking statements and the assumptions upon which they are based are reasonable, it can give no assurance that such expectations and assumptions will prove to have been correct. Forward-looking statements, which involve assumptions and describe our future plans, strategies, and expectations, are generally identifiable by use of the words may,” will,” should,” could,” expect,” anticipate,” estimate,” believe,” intend,” or project” or the negative of these words or other variations on these words or comparable terminology. The reader is cautioned not to put undue reliance on these forward-looking statements, as these statements are subject to numerous factors and uncertainties, including but not limited to: the timing and success of clinical and preclinical studies of product candidates, the potential timing and success of the Company’s product programs through their individual product development and regulatory approval processes, adverse economic conditions, intense competition, lack of meaningful research results, entry of new competitors and products, inadequate capital, unexpected costs and operating deficits, increases in general and administrative costs, termination of contracts or agreements, obsolescence of the Company’s technologies, technical problems with the Company’s research, price increases for supplies and components, litigation and administrative proceedings involving the Company, the possible acquisition of new businesses or technologies that result in operating losses or that do not perform as anticipated, unanticipated losses, the possible fluctuation and volatility of the Company’s operating results, financial condition and stock price, losses incurred in litigating and settling cases, dilution in the Company’s ownership of its business, adverse publicity and news coverage, inability to carry out research, development and commercialization plans, loss or retirement of key executives and research scientists, and other risks. There can be no assurance that further research and development will validate and support the results of our preliminary research and studies. Further, there can be no assurance that the necessary regulatory approvals will be obtained or that the Company will be able to develop commercially viable products on the basis of its technologies. In addition, other factors that could cause actual results to differ materially are discussed in the Company’s most recent Form 10-Q and Form 10-K filings with the Securities and Exchange Commission. These reports and filings may be inspected and copied at the Public Reference Room maintained by the U.S. Securities & Exchange Commission at 100 F Street, N.E., Washington, D.C. 20549. You can obtain information about operation of the Public Reference Room by calling the U.S. Securities & Exchange Commission at 1-800-SEC-0330. The U.S. Securities & Exchange Commission also maintains an Internet site that contains reports, proxy and information statements, and other information regarding issuers that file electronically with the U.S. Securities & Exchange Commission at http://www.sec.gov. The Company undertakes no obligation to publicly release the results of any revisions to these forward-looking statements that may be made to reflect the events or circumstances after the date hereof or to reflect the occurrence of unanticipated events.

Originally posted here:
RenovaCare Appoints Dr. Lydia M. Evans to Its Board of Directors and Increases Board Membership - Stockhouse

Recommendation and review posted by Bethany Smith

In the 1960s, Milford Graves became a groundbreaking drummer in avant-garde jazz, but intertwined with his career had been his constant study of musics impact on the human heart.

Now Mr. Graves, a 78-year-old who lives in Jamaica, Queens, has become his own subject: He has amyloid cardiomyopathy, sometimes called stiff heart syndrome.

Doctors have informed him that the condition, also called cardiac amyloidosis, has no cure. When he received the diagnosis in 2018, he was told he had six months to live.

Since then, Mr. Graves said, he has come close to death several times because of fluid filling his lungs. His legs too weakened to walk, he remains in a recliner in his living room with a tube feeding medicine to his heart and another draining fluid from his midsection.

But he has hardly surrendered to the illness. Although he is under the care of a cardiologist, he is also treating himself with the alternative techniques he has spent decades researching.

Since the 1970s, Mr. Graves has studied the heartbeat as a source of rhythm and has maintained that recording musicians most prevalent heart rhythms and pitches, and then incorporating those sounds into their playing, would help them produce more personal music.

He also believes that heart problems can be helped by recording a patients unhealthy heart and musically tweaking it into a healthier rhythm to use as biofeedback.

In recent months, Mr. Graves has been listening constantly to his own heart with a stethoscope and monitoring it with an ultrasound device he bought on eBay.

It turns out, I was studying the heart to prepare for treating myself, he said.

His diagnosis has only invigorated his research, musical explorations and creative output as a visual artist, said Mr. Graves, whose daily fight against the disease has become something of a performance art project.

He said he is rushing to further his research and organize it, so that it can be continued after his death by his students, who are fastidiously documenting and videotaping his daily activity, both for his archives and for an exhibition in September at the Institute of Contemporary Art in Philadelphia.

The shows curator, Mark Christman, visits Mr. Graves and gathers his latest work, from sculptures to customized drums to new videos of Mr. Graves playing.

Mr. Graves has no idea how long he will live It could be three days, it could be a month, or longer but he is adamant that he will be strong enough to play live for the show, perhaps streamed from his recliner.

Where some might see cruel irony in being afflicted by heart disease, which he has studied for 45 years, he sees a challenge.

Its like some higher power saying, OK, buddy, you wanted to study this, here you go, he said. Now the challenge is inside of me.

He wonders if he has somehow internalized the subject of his study.

I ask myself, Why did I get something that, in my research, Ive been trying to rectify? he said. Its a rare disease with very little research on it. The experts say theres nothing to be done, so I have to look inward for answers.

Mr. Graves has long said that a healthy heart beats with flexible, varying rhythms that respond to stimuli from the body. The rhythms, he said, bear similarities to some traditional Nigerian drumming styles, and he has fashioned some of his drumming approaches along these lines.

Because of the abnormal heartbeats caused by his disease, which stiffens the heart muscle and can lead to heart failure, what he hears now in his own heart is the sound of survival, he said.

It sounds less elastic and more plodding than before the diagnosis, he said, with a more metronomic regularity that he has called a rigid, unhealthy quality in a heartbeat.

He is practicing his biofeedback techniques by listening to his heart with a stethoscope and mimicking the rhythm and melody by singing and playing on a drum near his recliner. He also plays recordings of his own hearts sounds on the drumhead with the help of electronic transducers, effectively turning the drumhead into a speaker.

That has helped him come up with drumming techniques, including adjustments in drumhead tensions and new stick styles. Its still drum practice, but with higher stakes.

Mr. Graves has seen a resurgence in popularity in recent years, with exhibitions of his art and research, festival performances and an acclaimed full-length documentary, Milford Graves Full Mantis.

Instead of going into despair, his response was, Ive been asked to look deeper at this, said Jake Meginsky, the films co-director and a longtime assistant of Mr. Graves. Hes surviving this prognosis, and through his creative process hes offering us a record on what that survival is like.

Mr. Graves approach is no surprise to those familiar with his unconventional life path.

He grew up in the South Jamaica housing projects and in the 1960s played with such avant-garde musicians as Cecil Taylor and Albert Ayler, with whom he performed at John Coltranes funeral in 1967. He turned down offers from Miles Davis to join Daviss band.

In more recent years, he has also collaborated with the rocker Lou Reed, the pianist Jason Moran and the avant-garde saxophonist John Zorn.

Mr. Graves became a largely self-taught musician and scientific researcher, delving into herbal medicine, holistic healing, acupuncture, martial arts and other disciplines.

With only a high school diploma and minimal formal medical training, he taught music healing and drumming classes at Bennington College in Vermont for nearly 40 years before retiring in 2012.

He developed a martial-arts style modeled after the movements of the praying mantis and dance traditions from West African styles and the Lindy Hop.

He did pretty much everything on his own, and its very important that his work continue, so he wants to leave everything in the right places with the right people, his wife, Lois, said. He knows he has more work to do and hes going to get it done.

Since 1970, Mr. and Ms. Graves have lived in a home in Queens that he has decorated with a Gaudesque mosaic of stones and colored glass. The Graveses have turned the yard into a lush garden, dense with citrus trees, herbs and exotic plants. He converted a free-standing garage into an ornate temple that was often used as a dojo for martial arts.

But it is the basement where his heart research was mainly conducted. The space is packed with African idols, anatomical models, herbal extracts, African drums and a hodgepodge of heart-monitoring equipment displaying intricate electrocardiogram readouts.

Here, he said, he has treated students, neighbors and colleagues, and since 1990 has recorded perhaps 5,000 heartbeats. Mr. Graves created programs to analyze the hearts rhythms and pitches caused by muscle and valve movement. He found ways to amplify the more obscure patterns and complex melody lines in the vibration frequencies underneath the basic thump-THUMP heartbeat, and use them for both musical and medical analysis.

In 2000, he received a Guggenheim grant to purchase heart-monitoring equipment. And in 2017, he co-patented technology for using heart melodies to regenerate stem cells.

Dr. Baruch Krauss, who teaches pediatrics at Harvard Medical School and is an emergency physician at Boston Childrens Hospital, said Mr. Gravess work has a lot of potential and possibility if it were to be furthered in a clinical setting.

Theres a lot there to be studied and used as a basis for further research, said Dr. Krauss, who follows Mr. Gravess work.

Hes continuously inquisitive and creative and interested, he added, and this condition really hasnt slowed him down.

In his living room on a recent Sunday, one of Mr. Gravess students, Peyton Pleninger, 24, helped him set up a device to play heart sounds and assisted him with making an assemblage for the art show.

I dont want to leave the planet with things undone, Mr. Graves said.

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A Jazz Drummers Fight to Keep His Own Heart Beating - The New York Times

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Abstract:

Altered olfactory function is a common symptom of COVID-19, but its etiology is unknown. A key question is whether SARS-CoV-2 (CoV-2) the causal agent in COVID-19 affects olfaction directly, by infecting olfactory sensory neurons or their targets in the olfactory bulb, or indirectly, through perturbation of supporting cells. Here we identify cell types in the olfactory epithelium and olfactory bulb that express SARS-CoV-2 cell entry molecules. Bulk sequencing demonstrated that mouse, non-human primate and human olfactory mucosa expresses two key genes involved in CoV-2 entry, ACE2 and TMPRSS2. However, single cell sequencing revealed that ACE2 is expressed in support cells, stem cells, and perivascular cells, rather than in neurons. Immunostaining confirmed these results and revealed pervasive expression of ACE2 protein in dorsally-located olfactory epithelial sustentacular cells and olfactory bulb pericytes in the mouse. These findings suggest that CoV-2 infection of non-neuronal cell types leads to anosmia and related disturbances in odor perception in COVID-19 patients.

SARS-CoV-2 (CoV-2) is a pandemic coronavirus that causes the COVID-19 syndrome, which can include upper respiratory infection (URI) symptoms, severe respiratory distress, acute cardiac injury and death (1-4). CoV-2 is closely related to other coronaviruses, including the causal agents in pandemic SARS and MERS (SARS-CoV and MERS-CoV, respectively) and endemic viruses typically associated with mild URI syndromes (hCoV-OC43, hCoV-HKU1, hCoV-229E and hCoV-NL63) (5-7). Clinical reports suggest that infection with CoV-2 is associated with high rates of disturbances in smell and taste perception, including anosmia (8-13). While many viruses (including coronaviruses) induce transient changes in odor perception due to inflammatory responses, in at least some cases COVID-related anosmia has been reported to occur in the absence of significant nasal inflammation or coryzal symptoms (11, 14-16). Furthermore, recovery from COVID-related anosmia often occurs over weeks (11, 17, 18), while recovery from typical post-viral anosmia which is often caused by direct damage to olfactory sensory neurons (OSNs) frequently takes months (19-21). These observations suggest that CoV-2 might target odor processing through mechanisms distinct from those used by other viruses, although the specific means through which CoV-2 alters odor perception remains unknown.

CoV-2 like SARS-CoV infects cells through interactions between its spike (S) protein and the ACE2 protein on target cells. This interaction requires cleavage of the S protein, likely by the cell surface protease TMPRSS2, although other proteases (such as Cathepsin B and L, CTSB/CTSL) may also be involved (4-6, 22-25). Other coronaviruses use different cell surface receptors and proteases to facilitate cellular entry, including DPP4, FURIN and HSPA5 for MERS-CoV, ANPEP for HCoV-229E, TMPRSS11D for SARS-CoV (in addition to ACE2 and TMPRSS2), and ST6GAL1 and ST3GAL4 for HCoV-OC43 and HCoV-HKU1 (6, 26-28).

We hypothesized that identifying the specific cell types susceptible to direct CoV-2 infection (due to e.g., ACE2 and TMPRSS2 expression) would provide insight into possible mechanisms through which COVID-19 alters smell perception. The nasal epithelium is divided into a respiratory epithelium (RE) and olfactory epithelium (OE), whose functions and cell types differ. The nasal RE is continuous with the epithelium that lines much of the respiratory tract and is thought to humidify air as it enters the nose; main cell types include basal cells, ciliated cells, secretory cells (including goblet cells), and brush/microvillar cells (29, 30) (Fig. 1). The OE, in contrast, is responsible for odor detection, as it houses mature OSNs that interact with odors via receptors localized on their dendritic cilia. OSNs are supported by sustentacular cells, which act to structurally support sensory neurons, phagocytose and/or detoxify potentially damaging agents, and maintain local salt and water balance (31-33); microvillar cells and mucus-secreting Bowmans gland cells also play important roles in maintaining OE homeostasis and function (29, 34) (Fig. 1). In addition, the OE contains globose basal cells (GBCs), which are primarily responsible for regenerating OSNs during normal epithelial turnover, and horizontal basal cells (HBCs), which act as reserve stem cells activated upon tissue damage (35-37). Although studies defining the lineage relationships between GBCs, HBCs and their progeny have necessarily been performed in rodents, basal progenitor populations with similar transcriptional profiles are present in adult human olfactory epithelium, suggesting closely related homeostatic and injury-response mechanisms (37, 38). Odor information is conveyed from the OE to the brain by OSN axons, which puncture the cribriform plate at the base of the skull and terminate in the olfactory bulb (OB). Within the OB local circuits process olfactory information before sending it to higher brain centers (Fig. 1).

Sagittal view of the human nasal cavity, in which respiratory and olfactory epithelia are colored (left). For each type of epithelium, a schematic of the anatomy and known major cell types are shown (right). In the olfactory bulb in the brain (tan) the axons from olfactory sensory neurons coalesce into glomeruli, and mitral/tufted cells innervate these glomeruli and send olfactory projections to downstream olfactory areas. Glomeruli are also innervated by juxtaglomerular cells, a subset of which are dopaminergic.

It has recently been demonstrated through single cell RNA sequencing analysis (referred to herein as scSeq) that cells from the human upper airway including nasal RE goblet and ciliated cells express high levels of ACE2 and TMPRSS2, suggesting that these RE cell types may serve as a viral reservoir during CoV-2 infection (39, 40). However, analyzed samples in these datasets did not include any OSNs or sustentacular cells, indicating that tissue sampling in these experiments did not include the OE (41, 42). Here we query both new and previously published bulk RNA-Seq and scSeq datasets from the olfactory system for expression of ACE2, TMRPSS2 and other genes implicated in coronavirus entry. We find that non-neuronal cells in the OE and olfactory bulb, including support, stem and perivascular cells, express CoV-2 entry-associated transcripts and their associated proteins, suggesting that infection of these non-neuronal cell types contributes to anosmia in COVID-19 patients.

To determine whether genes relevant to CoV-2 entry are expressed in OSNs or other cell types in the human OE, we queried previously published bulk RNA-Seq data derived from the whole olfactory mucosa (WOM) of macaque, marmoset and human (43), and found expression of almost all CoV-entry-related genes in all WOM samples (Figure S1A). To identify the specific cell types in human OE that express ACE2, we quantified gene expression in scSeq derived from four human nasal biopsy samples recently reported by Durante et al. (38). Neither ACE2 nor TMPRSS2 were detected in mature OSNs, whereas these genes were detected in both sustentacular cells and HBCs (Fig. 2A-D and S1B-E). In contrast, genes relevant to cell entry of other CoVs were expressed in OSNs, as well as in other OE cell types. We confirmed the expression of ACE2 proteins via immunostaining of human olfactory epithelium biopsy tissue, which revealed expression in sustentacular and basal cells, and an absence of ACE2 protein in OSNs (Figs. 2E and S2). Together, these results demonstrate that sustentacular and olfactory stem cells, but not mature OSNs, are potentially direct targets of CoV-2 in the human OE.

Coronavirus cell entry-related genes are expressed in human respiratory and olfactory epithelium but are not detected in human OSNs. (A) UMAP representation of cell types in human nasal biopsy scSeq data from Durante et al. 2020 (38). Each dot represents an individual cell, colored by cell type (HBC = horizontal basal cell, OSN = olfactory sensory neuron, SUS = sustentacular cell, MV: microvillar cell, Resp.: respiratory, OEC = olfactory ensheathing cell, SMC=smooth muscle cell). (B) UMAP representations of 865 detected immature (GNG8) and mature (GNG13) OSNs. Neither ACE2 nor TMPRSS2 are detected in either population of OSNs. The color represents the normalized expression level for each gene (number of UMIs for a given gene divided by the total number of UMIs for each cell). (C) UMAP representations of all cells, depicting the normalized expression of CoV-2 related genes ACE2 and TMPRSS2, as well as several cell type markers. ACE2 and TMPRSS2 are expressed in respiratory and olfactory cell types, but not in OSNs. ACE2 and TMPRSS2 are detected in HBC (KRT5) and sustentacular (CYP2A13) cells, as well as other respiratory epithelial cell types, including respiratory ciliated (FOXJ1) cells. (D) Percent of cells expressing ACE2 and TMPRSS2. ACE2 was not detected in any OSNs, but was observed in sustentacular cells and HBCs, among other olfactory and respiratory epithelial cell types. Olfactory and respiratory cell types are shown separately. ACE2 and TMPRSS2 were also significantly co-expressed (Odds ratio 7.088, p-value 3.74E-57, Fishers exact test). (E) ACE2 immunostaining of human olfactory mucosal biopsy samples (taken from a 28-year old female). ACE2 protein (green) is detected in sustentacular cells and KRT5-positive HBCs (red; white arrowhead). Nuclei were stained with DAPI (blue). Bar = 25 m. The ACE2 and KRT5 channels from the box on the left are shown individually on the right.

Given that the nasopharynx is a major site of infection for CoV-2 (10), we compared the frequency of ACE2 and TMPRSS2 expression among the cell types in the human RE and OE (38). Sustentacular cells exhibited the highest frequency of ACE2 expression in the OE (2.9% of cells) although this frequency was slightly lower than that observed in respiratory ciliated and secretory cells (3.6% and 3.9%, respectively). While all HBC subtypes expressed ACE2, the frequency of expression of ACE2 was lower in olfactory HBCs (0.8% of cells) compared to respiratory HBCs (1.7% of cells) (Fig. 2D). In addition, all other RE cell subtypes showed higher frequencies of ACE2 and TMPRSS2 expression than was apparent in OE cells.

These results demonstrate the presence of key CoV-2 entry-related genes in specific cell types in the OE, but at lower levels of expression than in RE isolated from the human nasal mucosa. We wondered whether these lower levels of expression might nonetheless be sufficient for infection by CoV-2. It was recently reported that the nasal RE has higher expression of CoV-2 entry genes than the RE that lines the trachea or lungs (44), and we therefore asked where the OE fell within this previously established spectrum of expression. To address this question, we developed a two step alignment procedure in which we first sought to identify cell types that were common across the OE and RE, and then leveraged gene expression patterns in these common cell types to normalize gene expression levels across all cell types in the OE and RE (Figs. 3 and S3). This approach revealed a correspondences between submucosal gland goblet cells in the RE and Bowmans gland cells in the OE (96% mapping probability, see Methods), and between pulmonary ionocytes in the RE and a subset of microvillar cells in the OE (99% mapping probability, see Methods and Figure S3); after alignment, human OE sustentacular cells were found to express ACE2 and TMPRSS2 at levels similar to those observed in the remainder of the non-nasal respiratory tract (44) (Fig. 3C). As CoV-2 can infect cells in the lower respiratory tract (40, 45), these results are consistent with the possibility that specific cell types in the human olfactory epithelium express ACE2 at a level that is permissive for direct infection.

Coronavirus cell entry-related genes are expressed at comparable levels across respiratory and olfactory epithelial datasets. (A) Schematic of the mapping strategy used to identify similar cell types across datasets, applied to a toy example. Each cell type from Dataset 1 dataset is mapped to cell types from the Dataset 2. From left to right: Each Dataset 1 cell voted on its 5 most similar cells in Dataset 2; the total number of votes cast for each Dataset 2 cell type was quantified; and vote totals were Z-scored against 1000 shuffles where cell type labels were permutated. (B) Mapping was performed bi-directionally between the Deprez et al. (41) and Durante et al. (38) datasets, and the mapping Z-scores in each direction are compared. The set of cell type correspondences with high Z-scores (>25) in both directions are colored red (top). The set of cell type correspondences with high bi-directional mappings shown in red in top panel are highlighted in yellow (bottom). (C) Gene expression across cell types and tissues in Durante et al. (top) and Deprez et al. (bottom). Each gene is normalized to its maximum value across all tissues. Gene expression from Durante et al. was normalized to that in Deprez et al. to enable comparisons (see Methods and Figure S3). The tissues correspond to the indicated positions along the airway from nasal to distal lung. ACE2 expression in olfactory HBC and sustentacular cells is comparable to that observed in other cell types in the lower respiratory tract.

To further explore the distribution of CoV-2 cell entry genes in the olfactory system we turned to the mouse, which enables interrogative experiments not possible in humans. To evaluate whether mouse expression patterns correspond to those observed in the human OE, we examined published datasets in which RNA-Seq was independently performed on mouse WOM and on purified populations of mature OSNs (46-48). The CoV-2 receptor Ace2 and the protease Tmprss2 were expressed in WOM, as were the cathepsins Ctsb and Ctsl (Figs. 4A and S4A) (46). However, expression of these genes (with the exception of Ctsb) was much lower and Ace2 expression was nearly absent in purified OSN samples (Figs. 4A and S4A, see Legend for counts). Genes used for cell entry by other CoVs (except St3gal4) were also expressed in WOM, and de-enriched in purified OSNs. The de-enrichment of Ace2 and Tmprss2 in OSNs relative to WOM was also observed in two other mouse RNA-Seq datasets (47, 48) (Figure S4B). These data demonstrate that, as in humans, Ace2 and other CoV-2 entry-related genes are expressed in the mouse olfactory epithelium.

ACE2 is expressed in the mouse nasal epithelium but not in mature OSNs. (A) Log2-fold change (FC) in mean across-replicate gene expression between olfactory sensory neurons (OSNs) and whole olfactory mucosa (WOM) for coronavirus (CoV)-related genes and cell type markers (HBC = horizontal basal cells, SUS = sustentacular cells), data from Saraiva et al. (46). (B) UMAP representation of scSeq data from the WOM, colored by cell types (mOSN: mature OSN, iOSN: immature OSN, INP: immediate neural precursor, GBC: globose basal cell, MV: microvillar cell, Resp.: respiratory). (C) Percent of cells expressing Ace2 and Tmprss2 in olfactory and respiratory cell types in the WOM (Drop-seq) dataset. Detection was considered positive if any transcripts (UMIs) were expressed for a given gene. Sustentacular cells (SUS) from dorsal and ventral zones are quantified separately. Ace2 is detected in dorsal sustentacular, Bowmans gland, HBCs, as well as respiratory cell types. (D) UMAP representation of sustentacular cells, with expression of CoV-2 related genes Ace2 and Tmprss2, as well as marker genes for SUS (both pan-SUS marker Cbr2 and dorsal specific marker Sult1c1) indicated. The color represents the normalized expression level for each gene (number of UMIs for a given gene divided by the total number of UMIs for each cell; in this plot Ace2 expression is binarized for visualization purposes). Ace2-positive sustentacular cells are found within the dorsal Sult1c1-positive subset. UMAP plots for other cell types are shown in Figure S4.

The presence of Ace2 and Tmprss2 transcripts in mouse WOM and their (near total) absence in purified OSNs suggest that the molecular components that enable CoV-2 entry into cells are expressed in non-neuronal cell types in the mouse nasal epithelium. To identify the specific cell types that express Ace2 and Tmprss2, we performed scSeq (via Drop-seq, see Methods) on mouse WOM (Fig. 4B). These results were consistent with observations made in the human epithelium: Ace2 and Tmprss2 were expressed in a fraction of sustentacular and Bowmans gland cells, and a very small fraction of stem cells, but not in OSNs (zero of 17,666 identified mature OSNs, Figs. 4C and S4C-D). Of note, only dorsally-located sustentacular cells, which express the markers Sult1c1 and Acsm4, were positive for Ace2 (Figs. 4D and S4D-E). Indeed, reanalysis of the ACE2-positive subset of human sustentacular cells revealed that all positive cells expressed genetic markers associated with the dorsal epithelium (Figure S1D). An independent mouse scSeq data set (obtained using the 10x Chromium platform, see Methods) confirmed that olfactory sensory neurons did not express Ace2 (2 of 28,769 mature OSNs were positive for Ace2), while expression was observed in a fraction of Bowmans gland cells and HBCs (Figure S5, see Methods). Expression in sustentacular cells was not observed in this dataset, which included relatively few dorsal sustentacular cells (a possible consequence of the specific cell isolation procedure associated with the 10x platform; compare Figures S5C and 4D).

Staining of the mouse WOM with anti-ACE2 antibodies confirmed that ACE2 protein is expressed in sustentacular cells and is specifically localized to the sustentacular cell microvilli (Fig. 5). ACE2-positive sustentacular cells were identified exclusively within the dorsal subregion of the OE; critically, within that region many (and possibly all) sustentacular cells expressed ACE2 (Fig. 5B-E). Staining was also observed in Bowmans gland cells but not in OSNs, and in subsets of RE cells (Fig. 5F-G). Taken together, these data demonstrate that ACE2 is expressed by sustentacular cells that specifically reside in the dorsal epithelium in both mouse and human.

ACE2 protein is detected in the mouse olfactory and respiratory epithelium. (A) ACE2 immunostaining of mouse main olfactory epithelium. As shown in this coronal section, ACE2 protein is detected in the dorsal zone and respiratory epithelium. The punctate Ace2 staining beneath the epithelial layer is likely associated with vasculature. Bar = 500 m. Arrowheads depict the edges of ACE2 expression, corresponding to the presumptive dorsal zone (confirmed in G). Dashed boxes indicate the areas shown in B and G (left). (B) ACE2 protein is detected in the dorsal zone of the olfactory epithelium. Bar = 50 m. (C) Dorsal zone-specific expression of ACE2 in the olfactory epithelium was confirmed by co-staining with NQO1, a protein expressed in dorsal-zone OSNs. Bar = 50 m. (D) ACE2 signal in dorsal olfactory epithelium does not overlap with the cilia of olfactory sensory neurons, as visualized by CNGA2. Bar = 50 m. (E) High magnification image of the apical end of the olfactory epithelium reveals that ACE2 signal is localized at the tip of villi of sustentacular cells, visualized by Phalloidin (F-Actin), but does not overlap with cilia of olfactory sensory neurons, as visualized by Acetylated Tubulin (Ac. Tubulin). Bar = 10 m. (F) Bowmans glands, which span from the lamina propria to the apical surface (arrowheads), were positive for ACE2 staining. Bar = 50 m. (G) ACE2 expression in the respiratory epithelium was confirmed by co-staining with TUBB4. Bar = 50 m.

Viral injury can lead to broad changes in OE physiology that are accompanied by recruitment of stem cell populations tasked with regenerating the epithelium (35, 37, 49). To characterize the distribution of Ace2 expression under similar circumstances, we injured the OE by treating mice with methimazole (which ablates both support cells and OSNs), and then employed a previously established lineage tracing protocol to perform scSeq on HBCs and their descendants during subsequent regeneration (see Methods) (36). This analysis revealed that after injury Ace2 and Tmprss2 are expressed in subsets of sustentacular cells and HBCs, as well as in the activated HBCs that serve to regenerate the epithelium (Figs. 6A-C and S6A; note that activated HBCs express Ace2 at higher levels than resting HBCs). Analysis of the Ace2-positive sustentacular cell population revealed expression of dorsal epithelial markers (Fig. 6D). To validate these results, we re-analyzed a similar lineage tracing dataset in which identified HBCs and their progeny were subject to Smart-seq2-based deep sequencing, which is more sensitive than droplet-based scSeq methods (36). In this dataset, Ace2 was detected in more than 0.7% of GBCs, nearly 2% of activated HBCs and nearly 3% of sustentacular cells but was not detected in OSNs (Figures S6B). Immunostaining with anti-ACE2 antibodies confirmed that ACE2 protein was present in activated stem cells under these regeneration conditions (Fig. 6E). These results demonstrate that activated stem cells recruited during injury express ACE2 and do so at higher levels than those in resting stem cells.

ACE2 is expressed in the mouse nasal epithelium in an injury model. (A) UMAP representation of data from an scSeq HBC lineage dataset, which includes several timepoints after epithelial injury induced by methimazole (mOSN: mature OSN, iOSN: immature OSN, INP: immediate neural precursor, SUS: sustentacular cell, GBC: globose basal cell, HBC: horizontal basal cell, HBC*: activated or cycling HBCs. MV: microvillar cell, Resp.: respiratory). (B) UMAP representation of CoV-2 related genes Ace2 and Tmprss2, as well as marker genes for the HBC-derived cell types. The color represents normalized expression (number of UMIs for a given gene divided by the total number of UMIs for each cell). (C) Percent of cells expressing Ace2 and Tmprss2. Ace2 is detected in sustentacular cells, HBC, activated/cycling HBC and respiratory cells. (D) UMAP representation of all sustentacular cells, indicating the normalized expression of CoV-2 related genes Ace2 and Tmprss2, as well as sustentacular (Ermn) cell markers. Ace2-positive sustentacular cells are largely a subset of dorsal SUS cells, as identified via the expression of Sult1c1. Sult1c1-positive sustentacular cells have higher levels of Ace2 (p=1.87E-03, Mann-Whitney test) and Ace2-positive sustentacular cells have higher levels of Sult1c1 (p=8.06E-07, Mann-Whitney test). (E) ACE2 immunostaining of mouse nasal epithelium after methimazole treatment, together with cycling cell marker Ki67 and HBC marker KRT5. At 48 hours after treatment, ACE2 signal is detected in Ki67+/KRT5+ activated HBCs (top). At 96 hours after treatment, ACE2 signal is observed at the apical surface of Ki67+ cells (bottom). Some ACE2-positive cells express low levels of the HBC marker KRT5 and have immunostaining patterns similar to that of dorsal sustentacular cells, suggesting that they are sustentacular cells in the process of differentiating from their HBC precursors. Bar = 25 m.

Given the potential for the RE and OE in the nasal cavity to be directly infected with CoV-2, we assessed the expression of Ace2 and other CoV entry genes in the mouse olfactory bulb (OB), which is directly connected to OSNs via cranial nerve I (CN I); in principle, alterations in OB function could cause anosmia independently of functional changes in the OE. To do so, we performed scSeq (using Drop-seq, see Methods) on the mouse OB, and merged these data with a previously published OB scSeq analysis, yielding a dataset with nearly 50,000 single cells (50) (see Methods). This analysis revealed that Ace2 expression was absent from OB neurons and instead was observed only in vascular cells, predominantly in pericytes, which are involved in blood pressure regulation, maintenance of the blood-brain barrier, and inflammatory responses (51) (Figs. 7A-D and S7-8). Although other potential CoV proteases were expressed in the OB, Tmprss2 was not expressed.

Expression of coronavirus entry genes in mouse olfactory bulb. (A) UMAP visualization of OB scSeq highlighting the main cell classes and subtypes from two integrated scSeq datasets (see Methods). VIP, vasoactive intestinal peptide-expressing neurons; ETCs, external tufted cells; OPCs, oligodendrocyte precursor cells; IPCs, intermediate precursor cells; OECs, olfactory ensheathing cells. Cluster information is summarized in Figures S7-8. (B) UMAP representation of the vascular cell cluster showing expression of CoV-2 entry genes (Ace2 and Tmprss2) and Kcnj8, a pericyte marker. Color scale depicts log-normalized UMI counts. (C) Normalized gene expression of coronavirus entry genes and cell class markers in mouse olfactory bulb. Color scale shows scaled mean expression level per cell type, normalized by their maximum expression across cell types. Ace2 is specifically expressed in vascular cells. (D) Percent of cells expressing Ace2. Other vascular denotes all vascular cells excluding pericytes. Ace2 expression was only detected in vascular cell types. (E) Log2-normalized expression (Log2(TPM+1)) of coronavirus entry genes and dopaminergic neuron markers in manually sorted and deeply-sequenced single olfactory bulb dopaminergic neurons. (F) ACE2 immunostaining of the mouse main olfactory bulb. Left, section of olfactory bulb containing the glomerular layer (with example glomeruli circled), mitral cell layer (MCL) and granule cell layer (GCL). ACE2 protein is present in vascular mural cells but not in OB neurons or OSN axons. Boxes i and ii indicate the locations of enlarged images. Bar = 100 m. (i) enlarged image of glomerular layer (middle). ACE2 protein staining was restricted to vascular cells. Bar = 50 m. (ii) enlarged image of MCL (dashed line) and GCL showing the lack of ACE2 (right). Bar = 50 m. (G) An olfactory bulb section showing ACE2 protein is detected in PDGFRB-positive mural cells, including smooth muscle cells (SMC) and pericytes. Bar = 25 m.

We also performed Smart-seq2-based deep sequencing of single OB dopaminergic juxtaglomerular neurons, a population of local interneurons in the OB glomerular layer that (like tufted cells) can receive direct monosynaptic input from nasal OSNs (Figs. 7E and S9, see Methods); these experiments confirmed the virtual absence of Ace2 and Tmprss2 expression in this cell type. Immunostaining in the OB revealed that blood vessels expressed high levels of ACE2 protein, particularly in pericytes; indeed nearly all pericytes exhibited some degree of staining with ACE2 antibodies. Consistent with the scSeq results, staining was not observed in any neuronal cell type (Fig. 7F-G). These observations may also hold true for at least some other brain regions, as re-analysis of 10 deeply sequenced SMART-Seq2-based scSeq datasets from different regions of the nervous system demonstrated that Ace2 and Tmprss2 expression is almost completely absent from neurons, consistent with prior immunostaining results (52, 53) (Figure S10). Given the extensive similarities detailed above in expression patterns for ACE2 and TMPRSS2 in the mouse and human, these findings (from mouse experiments) suggest that OB neurons are likely not a primary site of infection, but that vascular pericytes may be sensitive to CoV-2

Here we show that subsets of OE sustentacular cells, HBCs, and Bowmans gland cells in both mouse and human samples express the CoV-2 receptor ACE2 and the spike protein protease TMPRSS2. Human OE sustentacular cells express these genes at levels comparable to those observed in lung cells. In contrast, we failed to detect ACE2 expression in mature OSNs at either the transcript or protein levels. Similarly, mouse vascular pericytes in the OB express ACE2, while we did not detect ACE2 in OB neurons. Thus primary infection of non-neuronal cell types rather than sensory or bulb neurons may be responsible for anosmia and related disturbances in odor perception in COVID-19 patients.

The identification of non-neuronal cell types in the OE and OB susceptible to CoV-2 infection suggests four possible, non-mutually-exclusive mechanisms for the acute loss of smell reported in COVID-19 patients. First, local infection of support and vascular cells in the nose and bulb could cause significant inflammatory responses (including cytokine release) whose downstream effects could block effective odor conduction, or alter the function of OSNs or OB neurons (14, 54). Second, damage to support cells (which are responsible for local water and ion balance) could indirectly influence signaling from OSNs to the brain (55). Third, damage to sustentacular cells and Bowmans gland cells in mouse models can lead to OSN death, which in turn could abrogate smell perception (56). Finally, vascular damage could lead to hypoperfusion and inflammation leading to changes in OB function.

Although scSeq revealed ACE2 transcripts in only a subset of OE cells, this low level of observed expression matches or exceeds that observed in respiratory cells types that are infected by CoV-2 in COVID-19 patients (39) (Fig. 3). Critically, immunostaining in the mouse suggests that ACE2 protein is (nearly) ubiquitously expressed in sustentacular cells in the dorsal OE, despite sparse detection of Ace2 transcripts using scSeq. Similarly, nearly all vascular pericytes also expressed ACE2 protein, although only a fraction of OB pericytes were positive for Ace2 transcripts when assessed using scSeq. Although Ace2 transcripts were more rarely detected than protein, there was a clear concordance at the cell type level: expression of Ace2 mRNA in a particular cell type accurately predicted the presence of ACE2 protein, while Ace2 transcript-negative cell types (including OSNs) did not express ACE2 protein. These observations are consistent with recent findings in the respiratory epithelium suggesting that scSeq substantially underestimates the fraction of a given cell type that expresses the Ace2 transcript, but that new Ace2-expressing cell types are not discovered with more sensitive forms of analysis (40). If our findings in the mouse OE translate to the human (a reasonable possibility given the precise match in olfactory cell types that express CoV-2 cell entry genes between the two species), then ACE2 protein is likely to be expressed in a significant subset of human sustentacular cells. Thus, there may be many olfactory support cells available for CoV-2 infection in the human epithelium, which in turn could recruit a diffuse inflammatory process. However, it remains possible that damage to the OE could be caused by more limited cell infection. For example, infection of subsets of sustentacular cells by the SDAV coronavirus in rats ultimately leads to disruption of the global architecture of the OE, suggesting that focal coronavirus infection may be sufficient to cause diffuse epithelial damage (56).

We observe that activated HBCs, which are recruited after injury, express Ace2 at higher levels than those apparent in resting stem cells. The natural history of CoV2-induced anosmia is only now being defined; while recovery of smell on timescales of weeks in many patients has been reported, it remains unclear whether in a subset of patients smell disturbances will be long-lasting or permanent (8-12, 57). While on its own it is unlikely that infection of stem cells would cause acute smell deficits, the capacity of CoV-2 to infect stem cells may play an important role in those cases in which COVID-19-associated anosmia is persistent, a context in which infection of stem cells could inhibit OE regeneration and repair over time.

Two anosmic COVID-19 patients have presented with fMRI-identified hyperintensity in both OBs that reverted to normal after resolution of the anosmia (58, 59), consistent with central involvement in at least some cases. Many viruses, including coronaviruses, have been shown to propagate from the nasal epithelium past the cribriform plate to infect the OB; this form of central infection has been suggested to mediate olfactory deficits, even in the absence of lasting OE damage (60-65). The rodent coronavirus MHV passes from the nose to the bulb, even though rodent OSNs do not express Ceacam1, the main MHV receptor (61, 66) (Figures S4C, S5E, S6A), suggesting that CoVs in the nasal mucosa can reach the brain through mechanisms independent of axonal transport by sensory nerves; interestingly, OB dopaminergic juxtaglomerular cells express Ceacam1 (Fig. 7E), which likely supports the ability of MHV to target the bulb and change odor perception. Although SARS-CoV has been shown to infect the OB in a transgenic mouse model that ectopically expresses human ACE2 (65), it is unclear to what extent similar results will be observed for CoV-2 in these and in recently-developed mouse models expressing human ACE2 that better recapitulate native expression patterns (67-69). One speculative possibility is that local seeding of the OE with CoV-2-infected cells can result in OSN-independent transfer of virions from the nose to the bulb, perhaps via the vascular supply shared between the OB and the OSN axons that comprise CN I. Although CN I was not directly queried in our datasets, it is reasonable to infer that vascular pericytes in CN I also express ACE2, which suggests a possible route of entry for CoV-2 from the nose into the brain. Given the absence of ACE2 in mouse OB neurons and the near-ubiquity of ACE2 expression in OB pericytes we speculate that any central olfactory dysfunction in COVID-19 is the secondary consequence of inflammation arising locally from pericytes, or in response to diffusable factors arising from more distant sources (51).

Multiple immunostaining studies reveal that ACE2 protein in the human brain is predominantly or exclusively expressed in vasculature (and specifically expressed within pericytes) (52, 53, 70), and many neurological symptoms associated with CoV-2 infection like stroke or altered consciousness are consistent with an underlying vasculopathy (71-76). In addition, human CSF samples have failed thus far to reveal CoV-2 RNA (73, 77), and autopsies from human patients have found that the brain contains the lowest levels of CoV-2 across organs sampled (78). On the other hand, multiple other studies have suggested that ACE2 may be expressed in human neurons and glia (79-82). Additionally, two recent studies in mouse models expressing human ACE2 have found CoV-2 in the brain after intranasal inoculation (67, 68), although neither specifically queried the OB; this work stands in contrast to results in a non-human primate model of COVID-19, in which nasal infection did not lead to the presence of identifiable CoV-2 antigens in the brain (83). Further work will be required to resolve these inconsistencies, and to definitively characterize the distribution of ACE2 protein and ultimately CoV2-infected cells in the human OB and brain.

We note several caveats that temper our conclusions. Although current data suggest that ACE2 is the most likely receptor for CoV-2 in vivo, it is possible (although it has not yet been demonstrated) that other molecules such as BSG may enable CoV-2 entry independently of ACE2 (84, 85) (Figures S1E, S4C, S5E, S6A). In addition, it has recently been reported that low level expression of ACE2 can support CoV-2 cell entry (86); it is possible, therefore, that ACE2 expression beneath the level of detection in our assays may yet enable CoV-2 infection of apparently ACE2 negative cell types. We also propose that damage to the olfactory system is either due to primary infection or secondary inflammation; it is possible (although has not yet been demonstrated) that cells infected with CoV-2 can form syncytia with cells that do not express ACE2. Such a mechanism could damage neurons adjacent to infected cells. Finally, it has recently been reported that inflammation can induce expression of ACE2 in human cells (87, 88). It is therefore possible that our survey of ACE2 expression, and other recent reports demonstrating expression of ACE2 in OE support and stem cells but not neurons (81, 89, 90), might under-represent the cell types that express ACE2 under conditions of CoV-2 infection.

Any reasonable pathophysiological mechanism for COVID-19-associated anosmia must account for the high penetrance of smell disorders relative to endemic viruses (12, 91, 92), the apparent suddenness of smell loss that can precede the development of other symptoms (11, 13), and the transient nature of dysfunction in many patients (11, 17, 18); definitive identification of the disease mechanisms underlying COVID-19-mediated anosmia will require additional research. Nonetheless, our identification of cells in the OE and OB expressing molecules known to be involved in CoV-2 entry illuminates a path forward for future studies.

Human scSeq data from Durante et al. (38) was downloaded from the GEO at accession GSE139522. 10x Genomics mtx files were filtered to remove any cells with fewer than 500 total counts. Additional preprocessing was performed as described above, including total counts normalization and filtering for highly variable genes using the SPRING gene filtering function filter_genes with parameters (90, 3, 10). The resulting data were visualized in SPRING and partitioned using Louvain clustering on the SPRING k-nearest-neighbor graph. Four clusters were removed for quality control, including two with low total counts (likely background) and two with high mitochondrial counts (likely stressed or dying cells). Putative doublets were also identified using Scrublet and removed (7% of cells). The remaining cells were projected to 40 dimensions using PCA. PCA-batch-correction was performed using Patient 4 as a reference, as previously described (93). The filtered data were then re-partitioned using Louvain clustering on the SPRING graph and each cluster was annotated using known marker genes, as described in (38). For example, immature and mature OSNs were identified via their expression of GNG8 and GNG13, respectively. HBCs were identified via the expression of KRT5 and TP63 and olfactory HBCs were distinguished from respiratory HBCs via the expression of CXCL14 and MEG3. Identification of SUS cells (CYP2A13, CYP2J2), Bowmans gland (SOX9, GPX3), and MV ionocytes-like cells (ASCL3, CFTR, FOXI1) was also performed using known marker genes. For visualization, the top 40 principal components were reduced to two dimensions using UMAP with parameters (n_neighbors=15, min_dist=0.4).

The filtered human scSeq dataset contained 33358 cells. Each of the samples contained cells from both the olfactory and respiratory epithelium, although the frequency of OSNs and respiratory cells varied across patients, as previously described (38). 295 cells expressed ACE2 and 4953 cells expressed TMPRSS2. Of the 865 identified OSNs, including both immature and mature cells, none of the cells express ACE2 and only 2 (0.23%) expressed TMPRSS2. In contrast, ACE2 was reliably detected in at least 2% and TMPRSS2 was expressed in close to 50% of multiple respiratory epithelial subtypes. The expression of both known cell type markers and known CoV-related genes was also examined across respiratory and olfactory epithelial cell types. For these gene sets, the mean expression in each cell type was calculated and normalized by the maximum across cell types.

Data from Deprez et al. (41) were downloaded from the Human Cell Atlas website (https://www.genomique.eu/cellbrowser/HCA/; Single-cell atlas of the airway epithelium (Grch38 human genome)). A subset of these data was combined with a subset of the Durante data for mapping between cell types. For the Deprez data, the subset consisted of samples from the nasal RE that belonged to a cell type with >20 cells, including Basal, Cycling Basal, Suprabasal, Secretory, Mucous Multiciliated cells, Multiciliated, SMS Goblet and Ionocyte. We observed two distinct subpopulations of Basal cells, with one of the two populations distinguished by expression of Cxcl14. The cells in this population were manually identified using SPRING and defined for downstream analysis as a separate cell type annotation called Basal (Cxcl14+). For the Durante data, the subset consisted of cells from cell types that had some putative similarity to cells in the Deprez dataset, including Olfactory HBC, Cycling respiratory HBC, Respiratory HBC, Early respiratory secretory cells, Respiratory secretory cells, Sustentacular cells, Bowmans gland, Olfactory microvillar cells.

To establish a cell type mapping:

1) Durante et al. (38) and Deprez et al. (41) data were combined and gene expression values were linearly scaled so that all cells across datasets had the same total counts. PCA was then performed using highly variable genes (n=1477 genes) and PCA-batch-correction (93) with the Durante et al. data as a reference set.

2) Mapping was then performed bidirectionally between the two datasets. Each cell from Dataset 1 voted for the 5 most similar cells in the Dataset 2, using distance in PCA space as the measure of similarity. A table T counting votes across cell types was then computed, where for cell type i in the Dataset 1 and cell type j in the Dataset 2,

Tij = {number of votes cast from cells of type i to cells of type j}Thus, if Dataset 1 has N cells, then T would count 5*N votes (Tij=5N)

3) The table of votes T was Z-scored against a null distribution, generated by repeating the procedure above 1000 times with shuffled cell type labels.

The resulting Z-scores were similar between the two possible mapping directions (Durante -> Deprez vs. Deprez -> Durante; R=0.87 Pearson correlation of mapping Z-scores). The mapping Z-scores were also highly robust upon varying the number of votes-cast per cell (R>0.98 correlation of mapping Z-scores upon changing the vote numbers to 1 or 50 as opposed to 5). Only cell-type correspondences with a high Z-score in both mapping directions (Z-score > 25) were used for downstream analysis.

To establish a common scale of gene expression between datasets, we restricted to cell type correspondences that were supported both by bioinformatic mapping and shared a nominal cell type designation based on marker genes. These included: Basal/suprabasal cells = respiratory HBCs from Durante et al., and basal and suprabasal cells from Deprez et al. Secretory cells = rly respiratory secretory cells and respiratory secretory cells from Durante et al., and secretory cells from Deprez et al. Multiciliated cells = respiratory ciliated cells from Durante et al., and multiciliated cells from Deprez et al.

We next sought a transformation of the Durante et al. data so that it would agree with the Deprez et al. data within the corresponding cell types identified above To account for differing normalization strategies applied to each dataset prior to download (log normalization and rescaling with cell-specific factors for Deprez et al. but not for Durante et al.), we used the following ansatz for the transformation, where the pseudocount p is a global latent parameter and the rescaling factors fi are fit to each gene separately. In the equation below, T denotes the transformation and eij represents a gene expression value for cell i and gene j in the Durante data:

The parameter p was fit by maximizing the correlation of average gene expression across all genes between each of the cell type correspondences listed above. The rescaling factors fi. were then fitted separately for each gene by taking the quotient of average gene expression between the Deprez et al. data and the log-transformed Durante et al. data, again across the cell type correspondences above.

Normalized gene expression tables were obtained from previous published datasets (43, 46-48) (Table 1). For the mouse data sets, the means of the replicates from WOM or OSN were used to calculate Log2 fold changes. For the mouse data from Saraiva et al. and the primate data sets (43, 46), the normalized counts of the genes of interest from individual replicates were plotted.

Three different mouse bulk RNA-seq datasets were used, each with replicates from WOM or purified OSNs. An additional dataset contained bulk RNA-seq data from humans and non-human primates.

Tissue dissection and single-cell dissociation for nasal epithelium. A new dataset of whole olfactory mucosa scSeq was generated from adult male mice (812 weeks-old). All mouse husbandry and experiments were performed following institutional and federal guidelines and approved by Harvard Medical Schools Institutional Animal Care and Use Committee (IACUC). Briefly, dissected main olfactory epithelium were cleaned up in 750 l of EBSS (Worthington) and epithelium tissues were isolated in 750 L of Papain (20 U/mL in EBSS) and 50 L of DNase I (2000 U/mL). Tissue pieces were transferred to a 5 mL round-bottom tube (BD) and 1.75 mL of Papain and 450 L of DNase I were added. After 11.5 hour incubation with rocking at 37C, the suspension was triturated with a 5 mL pipette 15 times and passed through 40 m cell strainer (BD) and strainer was washed with 1 mL of DMEM + 10% FBS (Invitrogen). The cell suspension was centrifuged at 300 g for 5 min. Cells were resuspended with 4 mL of DMEM + 10% FBS and centrifuged at 300 g for 5 min. Cells were suspended with PBS + 0.01% BSA and concentration was measured by hemocytometer.

Drop-seq experiments. Drop-seq experiments were performed as previously described (94). Microfluidics devices were obtained from FlowJEM and barcode beads were obtained from chemgenes. 8 of 15 min Drop-seq runs were collected in total, which were obtained from 5 mice.

Sequencing of Drop-seq samples. 8 replicates of Drop-seq samples were sequenced across 5 runs on an Illumina NextSeq 500 platform. Paired end reads from the fastq files were trimmed, aligned, and tagged via the Drop-seq tools (v1.13) pipeline, using STAR (v2.5.4a) with genomic indices from Ensembl Release 93. The digital gene expression matrix was generated for 4,000 cells for 0126_2, 5,000 cells for 0105, 0126_1, 051916_DS11, 051916_DS12, 051916_DS22, 5,500 cells for 051916_DS21, and 9,500 cells for 0106.

Preprocessing of Drop-seq samples. Processing of the WOM Drop-seq samples was performed in Seurat (v2.3.1). Cells with less than 500 UMIs or more than 15,000 UMIs, or higher than 5% mitochondrial genes were removed. Potential doublets were removed using Scrublet. Cells were initially preprocessed using the Seurat pipeline. Variable genes FindVariableGenes (y.cutoff = 0.6) were scaled (regressing out effects due to nUMI, the percent of mitochondrial genes, and replicate ids) and the data was clustered using 50 PCs with the Louvain algorithm (resolution=0.8). In a fraction of sustentacular cells, we observed co-expression of markers for sustentacular cells and other cell types (e.g., OSNs). Re-clustering of sustentacular cells alone separately out these presumed doublets from the rest of the sustentacular cells, and the presumed doublets were removed for the analyses described below.

Processing of Drop-seq samples. The filtered cells from the preprocessing steps were reanalyzed in python using Scanpy and SPRING. In brief, the raw gene counts in each cell were total counts normalized and variable genes were identified using the SPRING gene filtering function filter_genes with parameters (85, 3, 3); mitochondrial and olfactory receptor genes were excluded from the variable gene lists. The resulting 2083 variable genes were z-scored and the dimensionality of the data was reduced to 35 via principal component analysis. The k-nearest neighbor graph (n_neighbors=15) of these 35 PCs was clustered using the leiden algorithm (resolution=1.2) and was reduced to two dimensions for visualization via the UMAP method (min_dist=0.42). Clusters were manually annotated on the basis of known marker genes and those sharing markers (e.g., olfactory sensory neurons) were merged.

The mouse WOM Drop-seq dataset contained 29585 cells that passed the above filtering. Each of the 16 clusters identified contained cells from all 8 replicates in roughly equal proportions. Of the 17666 mature OSNs and the 4674 immature OSNs, none of the cells express Ace2. In contrast, in the olfactory epithelial cells, Ace2 expression was observed in the Bowmans gland, olfactory HBCs, dorsal sustentacular cells.

Mouse olfactory epithelium tissue processing. Mice were sacrificed with a lethal dose of xylazine and nasal epithelium with attached olfactory bulbs were dissected and fixed in 4% paraformaldehyde (Electron Microscope Sciences, 19202) in phosphate-buffered saline (PBS) for overnight at 4C or for 2 hours at room temperature. Tissues were washed in PBS for 3 times (5 min each) and incubated in 0.45M EDTA in PBS overnight at 4C. The following day, tissues were rinsed by PBS and incubated in 30% Sucrose in PBS for at least 30 min, transferred to Tissue Freezing Medium (VWR, 15146-025) for at least 45 min and frozen on crushed dry ice and stored at -80C until sectioning. Tissue sections (20 m thick for the olfactory bulb and 12 m thick for nasal epithelium) were collected on Superfrost Plus glass slides (VWR, 48311703) and stored at -80C until immunostaining.

For methimazole treated samples, Adult C57BL/6J mice (6-12 weeks old, JAX stock No. 000664) were given intraperitoneal injections with Methimazole (Sigma M8506) at 50 g/g body weight and sacrificed at 24, 48, and 96-hour timepoints.

Immunostaining for mouse tissue. Sections were permeabilized with 0.1% Triton X-100 in PBS for 20 min then rinsed 3 times in PBS. Sections were then incubated for 45-60 min in blocking solution that consisted of PBS containing 3% Bovine Serum Albumin (Jackson Immunoresearch, 001-000-162) and 3% Donkey Serum (Jackson ImmunoResearch, 017-000-121) at room temperature, followed by overnight incubation at 4C with primary antibodies diluted in the same blocking solution. Primary antibodies used are as follows. Goat anti-ACE2 (Thermo Fisher, PA5-47488, 1:40), mouse anti-TUBB4 (Sigma, T7941, 1:4000), rabbit anti-KRT5 (abcam, ab52635, 1:200), goat anti-NQO1 (abcam, ab2346, 1:200), mouse anti-acetylated Tubulin (abcam, ab24610, 1:500), rabbit anti-CNGA2 (abcam, ab79261, 1:100), rat anti-CD140b/PDGFRB (Thermo Fisher, 14-1402-82, 1:100).

On the following day, sections were rinsed once and washed three times for 5-10 min in PBS, then incubated for 45 min with secondary antibodies diluted in blocking solution at 1:300 ratios and/or Alexa 555-conjugated Phalloidin (1:400). Secondary antibodies used were as follows: Donkey anti-Goat IgG Alexa 488 (Jackson ImmunoResearch, 705-546-147), donkey anti-Goat IgG Alexa 555, (Invitrogen, A21432), donkey anti-Rabbit IgG Alexa 555 (Invitrogen, A31572), donkey anti-Rabbit IgG Alexa 647 (Jackson ImmunoResearch, 711-605-152), donkey anti-Mouse IgG Alexa 555 (Invitrogen, A31570), donkey anti-Mouse IgG Alexa 647 (Invitrogen, A31571), and donkey anti-Rat IgG Alexa 488 (Invitrogen, A21208).

After secondary antibody incubation, sections were washed twice for 5-10 min in PBS, incubated with 300 nM DAPI in PBS for 10 min and then rinsed with PBS. Slides were mounted with glass coverslips using Vectashield Mounting Medium (Vector Laboratories, H-1000) or ProLong Diamond Antifade Mountant (Invitrogen, P36961).

For co-staining of ACE2 and NQO1, slides were first stained with ACE2 primary antibody and donkey anti-Goat IgG Alexa 488 secondary. After 3 washes of secondary antibody, tissues were incubated with unconjugated donkey anti-Goat IgG Fab fragments (Jackson ImmunoResearch, 705-007-003) at 30 g/mL diluted in blocking solution for 1 hour at room temperature. Tissues were washed twice with PBS, once in blocking solution, and incubated in blocking solution for 30-40 min at room temperature, followed by a second round of staining with the NQO1 primary antibody and donkey anti-Goat IgG Alexa 555 secondary antibody.

Confocal images were acquired using a Leica SPE microscope (Harvard Medical School Neurobiology Imaging Facility) with 405 nm, 488 nm, 561 nm, and 635 nm laser lines. Multi-slice z-stack images were acquired, and their maximal intensity projections are shown. For Fig. 5A, tiled images were acquired and stitched by the Leica LAS X software. Images were processed using Fiji ImageJ software (95), and noisy images were median-smoothed using the Remove Outliers function built into Fiji.

Fluorescent in situ hybridization for mouse tissue. Sult1c1 RNA was detected by fluorescent RNAscope assay (Advanced Cell Diagnostics, kit 320851) using probe 539921-C2, following the manufacturers protocol (RNAscope Fluorescent Multiplex Kit User Manual, 320293-UM Date 03142017) for paraformaldehyde-fixed tissue. Prior to initiating the hybridization protocol, the tissue was pre-treated with two successive incubations (first 30 min, then 15 min long) in RNAscope Protease III (Advanced Cell Diagnostics, 322337) at 40C, then washed in distilled water. At the end of protocol, the tissue was washed in PBS and subjected to the 2-day immunostaining protocol described above.

Immunostaining of human nasal tissue. Human olfactory mucosa biopsies were obtained via IRB-approved protocol at Duke University School of Medicine, from nasal septum or superior turbinate during endoscopic sinus surgery. Tissue was fixed with 4% paraformaldehyde and cryosectioned at 10 m and sections were processed for immunostaining, as previously described (38).

Sections from a 28-year old female nasal septum biopsy were stained for ACE2 (Fig. 2E) using the same Goat anti-ACE2 (Thermo Fisher, PA5-47488, 1:40) and the protocol described above for mouse tissue. The human sections were co-stained with Rabbit anti-keratin 5 (Abcam, ab24647; AB_448212, 1:1000) and were detected with AlexaFluor 488 Donkey anti-goat (Jackson ImmunoResearch, 705-545-147) and AlexaFluor 594 Donkey anti-rabbit (Jackson ImmunoResearch, 711-585-152) secondary antibodies (1:300).

As further validation of ACE2 expression and to confirm the lack of ACE2 expression in human olfactory sensory neurons (Figure S2), sections were stained with a rabbit anti-ACE2 (Abcam, ab15348; RRID:AB_301861, used at 1:100) antibody immunogenized against human ACE2 and a mouse Tuj1 antibody against neuron-specific tubulin (BioLegend, 801201; RRID:AB_2313773). Anti-ACE2 was raised against a C-terminal synthetic peptide for human ACE2 and was validated by the manufacturer to not cross-react with ACE1 for immunohistochemical labeling of ACE2 in fruit bat nasal tissue as well as in human lower airway. Recombinant human ACE2 abolished labeling with this antibody in a previous study in human tissue, further demonstrating its specificity (53). The Tuj1 antibody was validated, as previously described (38). Biotinylated secondary antibodies (Vector Labs), avidin-biotinylated horseradish peroxidase kit (Vector) followed by fluorescein tyramide signal amplification (Perkin Elmer) were applied per manufacturers instructions. For dual staining, Tuj1 was visualized using AlexaFluor 594 Goat anti-Mouse (Jackson ImmunoResearch, 115-585-146; RRID: AB_2338881).

Human sections were counterstained with 4,6-diamidino-2-phenylindole (DAPI) and coverslips were mounted using Prolong Gold (Invitrogen) for imaging, using a Leica DMi8 microscope system. Images were processed using Fiji ImageJ software (NIH). Scale bars were applied directly from the Leica acquisition software metadata in ImageJ Tools. Unsharp Mask was applied in ImageJ, and brightness/contrast was adjusted globally.

Mice. 2 month-old and 18 month-old wild type C57BL/6J mice were obtained from the National Institute on Aging Aged Rodent Colony and used for the WOM experiments; each experimental condition consisted of one male and one female mouse to aid doublet detection. Mice containing the transgenic Krt5-CreER(T2) driver (96) and Rosa26-YFP reporter allele (97) were used for the HBC lineage tracing dataset. All mice were assumed to be of normal immune status. Animals were maintained and treated according to federal guidelines under IACUC oversight at the University of California, Berkeley.

Single-Cell RNA Sequencing. The olfactory epithelium was surgically removed, and the dorsal, sensory portion was dissected and dissociated, as previously described (36). For WOM experiments, dissociated cells were subjected to fluorescence-activated cell sorting (FACS) using propidium iodide to identify and select against dead or dying cells; 100,000 cells/sample were collected in 10% FBS. For the HBC lineage tracing experiments Krt5-CreER; Rosa26YFP/YFP mice were injected once with tamoxifen (0.25 mg tamoxifen/g body weight) at P21-23 days of age and sacrificed at 24 hours, 48 hours, 96 hours, 7 days and 14 days post-injury, as previously described (36, 98). For each experimental time point, YFP+ cells were isolated by FACS based on YFP expression and negative for propidium iodide, a vital dye.

Cells isolated by FACS were subjected to single-cell RNA-seq. Three replicates (defined here as a FACS collection run) per age were analyzed for the WOM experiment; at least two biological replicates were collected for each experimental condition for the HBC lineage tracing experiment. Single cell cDNA libraries from the isolated cells were prepared using the Chromium Single Cell 3 System according to the manufacturers instructions. The WOM preparation employed v3 chemistry with the following modification: the cell suspension was directly added to the reverse transcription master mix, along with the appropriate volume of water to achieve the approximate cell capture target. The HBC lineage tracing experiments were performed using v2 chemistry. The 0.04% weight/volume BSA washing step was omitted to minimize cell loss. Completed libraries were sequenced on Illumina HiSeq4000 to produce paired-end 100nt reads.

Sequence data were processed with the 10x Genomics Cell Ranger pipeline (2.0.0 for v2 chemistry), resulting in the initial starting number before filtering of 60,408 WOM cells and 25,469 HBC lineage traced cells. The scone R/Bioconductor package (99) was used to filter out lowly-expressed genes (fewer than 2 UMIs in fewer than 5 cells) and low-quality libraries (using the metric_sample_filter function with arguments hard_nreads = 2000, zcut = 4).

Preliminary Filtering. Cells with co-expression of male (Ddx3y, Eif2s3y, Kdm5d, and Uty) and female marker genes (Xist) were removed as potential doublets from the WOM dataset. For both datasets, doublet cell detection was performed per sample using DoubletFinder (100) and Scrublet (101). Genes with at least 3 UMIs in at least 5 cells were used for downstream clustering and cell type identification. For the HBC lineage tracing dataset, the Bioconductor package scone was used to pick the top normalization (none,fq,ruv_k=1,no_bio,batch), corresponding to full quantile normalization, batch correction and removing one factor of unwanted variation using RUV (102). A range of cluster labels were created by clustering using the partitioning around medoids (PAM) algorithm and hierarchical clustering in the clusterExperiment Bioconductor package (103), with parameters k0s= (10, 13, 16, 19, 22, 25) and alpha=(NA,0.1,0.2,0.3). Clusters that did not show differential expression were merged (using the function mergeClusters with arguments mergeMethod = adjP, cutoff = 0.01, and DEMethod = limma for the lineage-traced dataset). Initial clustering identified one Macrophage (Msr1+) cluster consisting of 252 cells; upon its removal and restarting from the normalization step a subsequent set of 15 clusters was obtained. These clusters were used to filter out 1515 cells for which no stable clustering could be found (i.e., unassigned cells), and four clusters respectively consisting of 31, 29 and 23 and 305 cells. Doublets were identified using DoubletFinder and 271 putative doublets were removed. Inspection of the data in a three-dimensional UMAP embedding identified two groups of cells whose experimentally sampled timepoint did not match their position along the HBC differentiation trajectory, and these additional 219 cells were also removed from subsequent analyses.

Analysis of CoV-related genes in WOM and HBC lineage 10x datasets. Analysis of WOM scSeq data were performed in python using the open-source Scanpy software starting from the raw UMI count matrix of the 40179 cells passing the initial filtering and QC criteria described above. UMIs were total-count normalized and scaled by 10,000 (TPT, tag per ten-thousands) and then log-normalized. For each gene, the residuals from linear regression models using the total number of UMIs per cell as predictors were then scaled via z-scoring. PCA was then performed on a set of highly-variable genes (excluding OR genes) calculated using the highly_variable_genes function with parameters: min_mean=0.01, max_mean=10, min_disp=0.5. A batch corrected neighborhood graph was constructed by the bbknn function with 42 PCs with the parameters: local_connectivity=1.5, and embedding two-dimensions using the UMAP function with default parameters (min_dist = 0.5). Cells were clustered using the neighborhood graph via the Leiden algorithm (resolution = 1.2). Identified clusters were manually merged and annotated based on known marker gene expression. We removed 281 cells containing mixtures of marker genes with no clear gene expression signature. The identified cell types and the number of each of the remaining 39898 cells detected were as follows. 28,769 mOSN: mature OSN; 2,607 iOSN: immature OSN; 859 INP: Immediate Neural Precursor; 623 GBC: Globose Basal Cell; HBC: Horizontal Basal Cell (1,083 Olfactory and 626 Respiratory); 480 SUS: sustentacular cell; 331 BG: Bowmans gland; MV: Microvillar cell (563 Brush-like and 1,530 Ionocyte-like); 92 OEC: Olfactory Ensheathing Cell; 76 Resp. Secretory cells; 227 Resp. unspecified cells; 172 atypical OSN; 1,757 various immune cells, 103 RBC: Red Blood Cell. TPT gene expression levels were visualized in two-dimensional UMAP plots.

The filtered HBC lineage dataset containing 21722 cells was analyzing in python and processed for visualization using pipelines in SPRING and Scanpy (104, 105). In brief, total counts were normalized to the median total counts for each cell and highly variable genes were selected using the SPRING gene filtering function (filter_genes) using parameters (90, 3, 3). The dimensionality of the data was reduced to 20 using principal components analysis (PCA) and visualized in two-dimensions using the UMAP method with parameters (n_neighbors=20, min_dist=0.5). Clustering was performed using the Leiden algorithm (resolution=1.45) and clusters were merged manually using known marker genes. The identified cell types and number of each type were: 929 mOSN: mature OSN; 2073 iOSN: immature OSN; 786 INP: Immediate Neural Precursor; 755 GBC: Globose Basal Cell; HBC: Horizontal Basal Cell (7782 Olfactory, 5418 Regenerating, and 964 Respiratory); 2666 SUS: sustentacular cell; and 176 Ionocyte-like Microvillar (MV) cell.

Expression of candidate CoV-2-related genes was defined if at least one transcript (UMI) was detected in that cell, and the percent of cells expressing candidate genes was calculated for each cell type. In the WOM dataset Ace2 was only detected in 2 out of 28,769 mature OSNs (0.007%), and in the HBC lineage dataset, Ace2 was not detected in any OSNs. Furthermore, Ace2 was not detected in immature sensory neurons (GBCs, INPs, or iOSNs) in either dataset.

Single-cell RNA-seq data from HBC-derived cells from Fletcher et al. and Gadye et al. (36, 98), labeled via Krt5-CreER driver mice, were downloaded from GEO at accession GSE99251 using the file GSE95601_oeHBCdiff_Cufflinks_eSet_counts_table.txt.gz. Processing was performed as described above, including total counts normalization and filtering for highly variable genes using the SPRING gene filtering function filter_genes with parameters (75, 20, 10). The resulting data were visualized in SPRING and a subset of cells were removed for quality control, including a cluster of cells with low total counts and another with predominantly reads from ERCC spike-in controls. Putative doublets were also identified using Scrublet and removed (6% of cells) (101). The resulting data were visualized in SPRING and partitioned using Louvain clustering on the SPRING k-nearest-neighbor graph using the top 40 principal components. Cell type annotation was performed manually using the same set of markers genes listed above. Three clusters were removed for quality control, including one with low total counts and one with predominantly reads from ERCC spike-in controls (likely background), and one with high mitochondrial counts (likely stressed cells). For visualization, and clustering the remaining cells were projected to 15 dimensions using PCA and visualized with UMAP with parameters (n_neighbors=15, min_dist=0.4, alpha=0.5, maxiter=500). Clustering was performed using the Leiden algorithm (resolution=0.4) and cell types were manually annotated using known marker genes.

The filtered dataset of mouse HBC-derived cells contained 1450 cells. The percent of cells expressing each marker gene was calculated as described above. Of the 51 OSNs identified, none of them expressed Ace2, and only 1 out of 194 INPs and iOSNs expressed Ace2. In contrast, Ace2 and Tmprss2 were both detected in HBCs and SUS cells.

Juvenile mouse data. Single-cell RNAseq data from whole mouse olfactory bulb (50) were downloaded from mousebrain.org/loomfiles_level_L1.html in loom format (l1 olfactory.loom) and converted to a Seurat object. Samples were obtained from juvenile mice (age postnatal day 26-29). This dataset comprises 20514 cells passing cell quality filters, excluding 122 cells identified as potential doublets.

Tissue dissection and single-cell dissociation. A new dataset of whole olfactory bulb scSeq was generated from adult male mice (812 weeks-old). All mouse husbandry and experiments were performed following institutional and federal guidelines and approved by Harvard Medical Schools Institutional Animal Care and Use Committee (IACUC). Briefly, dissected olfactory bulbs (including the accessory olfactory bulb and fractions of the anterior olfactory nucleus) were dissociated in 750 l of dissociation media (DM: HBSS containing 10mM HEPES, 1 mM MgCl2, 33 mM D-glucose) with 28 U/mL Papain and 386 U/mL DNase I (Worthington). Minced tissue pieces were transferred to a 5 mL round-bottom tube (BD). DM was added to a final volume of 3.3 mL and the tissue was mechanically triturated 5 times with a P1000 pipette tip. After 1-hour incubation with rocking at 37C, the suspension was triturated with a 10 mL pipette 10 times and 2.3 mL was passed through 40 m cell strainer (BD). The suspension was then mechanically triturated with a P1000 pipette tip 10 times and 800 L were filtered on the same strainer. The cell suspension was further triturated with a P200 pipette tip 10 times and filtered. 1 mL of Quench buffer (22 mL of DM, 2.5 mL of protease inhibitor prepared by resuspending 1 vial of protease inhibitor with 32 mL of DM, and 2000U of DNase I) was added to the suspension and centrifuged at 300 g for 5 min. Cells were resuspended with 3 mL of Quench buffer and overlaid gently on top of 5 mL of protease inhibitor, then spun down at 70 g for 10min. The pellet was resuspended using DM supplemented with 0.04% BSA and spun down at 300 g for 5 min. Cells were suspended in 400 L of DM with 0.04% BSA.

Olfactory bulb Drop-seq experiments. Drop-seq experiments were performed as previously described (94). Microfluidics devices were obtained from FlowJEM and barcode beads were obtained from chemgenes. Two 15 min Drop-seq runs were collected from a single dissociation preparation obtained from 2 mice. Two such dissociations were performed, giving 4 total replicates.

Sequencing of Drop-seq samples. 4 replicates of Drop-seq samples were pooled and sequenced across 3 runs on an Illumina NextSeq 500 platform. Paired end reads from the fastq files were trimmed, aligned, and tagged via the Drop-seq tools (1-2.0) pipeline, using STAR (2.4.2a) with genomic indices from Ensembl Release 82. The digital gene expression matrix was generated for 8,000 cells per replicate.

Preprocessing of Drop-seq samples. Cells with low numbers of genes (500), low numbers of UMIs (700) or high numbers of UMIs (>10000) were removed (6% of cells). Potential doublets were identified via Scrublet and removed (3.5% of cells). Overall, this new dataset comprised 27004 cells.

Integration of whole olfactory bulb scRNAseq datasets. Raw UMI counts from juvenile and adult whole olfactory bulb samples were integrated in Seurat (106). Integrating the datasets ensured that clusters with rare cell types could be identified and that corresponding cell types could be accurately matched. As described below (see Figure S7), although some cell types were observed with different frequencies, the integration procedure yielded stable clusters with cells from both datasets. Briefly, raw counts were log-normalised separately and the 10000 most variable genes identified by variance stabilizing transformation for each dataset. The 4529 variable genes present in both datasets and the first 30 principal components (PCs) were used as features for identifying the integration anchors. The integrated expression matrix was scaled and dimensionality reduced using PCA. Based on their percentage of explained variance, the first 28 PCs were chosen for UMAP visualization and clustering.

Graph-based clustering was performed using the Louvain algorithm following the standard Seurat workflow. Cluster stability was analyzed with Clustree on a range of resolution values (0.4 to 1.4), with 0.6 yielding the most stable set of clusters (107). Overall, 26 clusters were identified, the smallest of which contained only 43 cells with gene expression patterns consistent with blood cells, which were excluded from further visualization plots. Clustering the two datasets separately yielded similar results. Moreover, the distribution of cells from each dataset across clusters was homogenous (Figure S7) and the clusters corresponded previous cell class and subtype annotations (50). As previously reported, a small cluster of excitatory neurons (cluster 13) contained neurons from the anterior olfactory nucleus. UMAP visualizations of expression level for cell class and cell type markers, and for genes coding for coronavirus entry proteins, depict log-normalized UMI counts. The heatmap in Fig. 7C shows the mean expression level for each cell class, normalised to the maximum mean value. The percentage of cells per cell class expressing Ace2 was defined as the percentage of cells with at least one UMI. In cells from both datasets, Ace2 was enriched in pericytes but was not detected in neurons.

Tissue dissociation and manual cell sorting. Acute olfactory bulb 300 m slices were obtained from Dat-Cre/Flox-tdTomato (B6.SJL-Slc6a3tm1.1(cre) Bkmn/J, Jax stock 006660 / B6.Cg Gt(ROSA)26Sortm9(CAG-tdTomato)Hze, Jax stock 007909) P28 mice as previously described (108). As part of a wider study, at P27 these mice had undergone brief 24 hours unilateral naris occlusion via a plastic plug insert (N = 5 mice) or were subjected to a sham control manipulation (N = 5 mice); all observed effects here were independent of these treatment groups. Single cell suspensions were generated using the Neural Tissue Dissociation Kit Postnatal Neurons (Miltenyi Biotec. Cat no. 130-094-802), following manufacturers instructions for manual dissociation, using 3 fired-polished Pasteur pipettes of progressively smaller diameter. After enzymatic and mechanical dissociations, cells were filtered through a 30 m cell strainer, centrifuged for 10 min at 4C, resuspended in 500 l of ACSF (in mM: 140 NaCl, 1.25 KCl, 1.25 NaH2PO4, 10 HEPES, 25 Glucose, 3 MgCl2, 1 CaCl2) with channel blockers (0.1 M TTX, 20 M CNQX, 50 M D-APV) and kept on ice to minimise excitotoxicity and cell death.

For manual sorting of fluorescently labeled dopaminergic neurons we adapted a previously described protocol (109). 50 l of single cell suspension was dispersed on 3.5mm petri dishes (with a Sylgard-covered base) containing 2 ml of ACSF + channel blockers. Dishes were left undisturbed for 15 min to allow the cells to sink and settle. Throughout, dishes were kept on a metal plate on top of ice. tdTomato-positive cells were identified by their red fluorescence under a stereoscope. Using a pulled glass capillary pipette attached to a mouthpiece, individual cells were aspirated and transferred to a clean, empty dish containing 2 ml ACSF + channel blockers. The same cell was then transferred to a third clean plate, changing pipettes for every plate change. Finally, each individual cell was transferred to a 0.2 ml PCR tube containing 2 l of lysis buffer (RLT Plus - Qiagen). The tube was immediately placed on a metal plate sitting on top of dry ice for flash-freezing. Collected cells were stored at -80C until further processing. Positive (more than 10 cells) and negative (sample collection procedure without picking a cell) controls were collected for each sorting session. In total, we collected samples from 10 mice, averaging 50 tdTomato-positive cells collected per session. Overall, less than 2.5 hours elapsed between mouse sacrifice and collection of the last cell in any session.

Preparation and amplification of full-length cDNA and sequencing libraries. Samples were processing using a modified version of the Smart-Seq2 protocol(110). Briefly, 1 l of a 1:2,000,000 dilution of ERCC spike-ins (Invitrogen. Cat. no. 4456740) was added to each sample and mRNA was captured using modified oligo-dT biotinylated beads (Dynabeads, Invitrogen). PCR amplification was performed for 22 cycles. Amplified cDNA was cleaned with a 0.8:1 ratio of Ampure-XP beads (Beckman Coulter). cDNAs were quantified on Qubit using HS DNA reagents (Invitrogen) and selected samples were run on a Bioanalyzer HS DNA chip (Agilent) to evaluate size distribution.

For generating the sequencing libraries, individual cDNA samples were normalised to 0.2ng/l and 1l was used for one-quarter standard-sized Nextera XT (Illumina) tagmentation reactions, with 12 amplification cycles. Sample indexing was performed using index sets A and D (Illumina). At this point, individual samples were pooled according to their index set. Pooled libraries were cleaned using a 0.6:1 ratio of Ampure beads and quantified on Qubit using HS DNA reagents and with the KAPA Library Quantification Kits for Illumina (Roche). Samples were sequenced on two separate rapid-runs on HiSeq2500 (Illumina), generating 100bp paired-end reads. An additional 5 samples were sequenced on MiSeq (Illumina).

Full-length cDNA sequencing data processing and analysis. Paired-end read fastq files were demultiplexed, quality controlled using FastQC (https://www.bioinformatics.babraham.ac.uk/projects/fastqc/) and trimmed using Trim Galore (https://www.bioinformatics.babraham.ac.uk/projects/trim_galore/). Reads were pseudoaligned and quantified using kallisto (111) against a reference transcriptome from Ensembl Release 89 (Gencode Release M17 GRCm38.p6) with sequences corresponding to the ERCC spike-ins and the Cre recombinase and tdT genes added to the index. Transcripts were collapsed into genes using the sumAcrossFeatures function in scater.

Cell level quality control and cell filtering was performed in scater (112). Cells with <1000 genes, <100,000 reads, >75% reads mapping to ERCC spike-ins, >10% reads mapping to mitochondrial genes or low library complexity were discarded (14% samples). The population of olfactory bulb cells labeled in DAT-tdTomato mice is known to include a minor non-dopaminergic calretinin-positive subgroup (113), so calretinin-expressing cells were excluded from all analyses. The scTransform function in Seurat was used to remove technical batch effects.

An analysis of single-cell gene expression data from 10 studies was performed to investigate the expression of genes coding for coronavirus entry proteins in neurons from a range of brain regions and sensory systems. Processed gene expression data tables were obtained from scSeq studies that evaluated gene expression in retina (GSE81905) (114) inner ear sensory epithelium (GSE115934) (115, 116) and spiral ganglion (GSE114997) (117), ventral midbrain (GSE76381) (118), hippocampus (GSE100449) (119), cortex (GSE107632) (120), hypothalamus (GSE74672) (121), visceral motor neurons (GSE78845) (122), dorsal root ganglia (GSE59739) (123) and spinal cord dorsal horn (GSE103840) (124). Smart-Seq2 sequencing data from Vsx2-GFP positive cells was used from the retina dataset. A subset of the expression matrix that corresponds to day 0 (i.e., control, undisturbed neurons) was used from the layer VI somatosensory cortex dataset. A subset of the data containing neurons from untreated (control) mice was used from the hypothalamic neuron dataset. From the ventral midbrain dopaminergic neuron dataset, a subset comprising DAT-Cre/tdTomato positive neurons from P28 mice was used. A subset comprising Type I neurons from wild type mice was used from the spiral ganglion dataset. The unclassified neurons were excluded from the visceral motor neuron dataset. A subset containing neurons that were collected at room temperature was used from the dorsal root ganglia dataset. Expression data from dorsal horn neurons obtained from C57/BL6 wild type mice, vGat-cre-tdTomato and vGlut2-eGFP mouse lines was used from the spinal cord dataset. Inspection of all datasets for batch effects was performed using the scater package (version 1.10.1) (112). Publicly available raw count expression matrices were used for the retina, hippocampus, hypothalamus, midbrain, visceral motor neurons and spinal cord datasets, whereas the normalized expression data was used from the inner ear hair cell datasets. For datasets containing raw counts, normalization was performed for each dataset separately by computing pool-based size factors that are subsequently deconvolved to obtain cell-based size factors using the scran package (version 1.10.2) (125). Violin plots were generated in scater.

S. H. R. Bagheri, A. M. Asghari, M. Farhadi, A. R. S. Shamshiri, A. Kabir, S.K. Kamrava, M. Jalessi, A. Mohebbi, R. Alizadeh, A.A.Honormand, Coincidence of COVID-19 epidemic and olfactory dysfunction outbreak. medRxiv 20041889, 27 March 2020. .doi:10.1101/2020.03.23.20041889

V. Parma et al., More than smell. COVID-19 is associated with severe impairment of smell, taste, and chemesthesis. medRxiv, 20090902 24 May 2020.

H. J. Hedrich, The Laboratory Mouse. (Academic Press, 2012), pp. 845.

M. Deprez et al., A single-cell atlas of the human healthy airways. bioRxiv 884759 23 December 2019.

W. Sungnak, N. Huang, C. Bcavin, M. Berg, H. C. A. L. B. Network, SARS-CoV-2 entry genes are most highly expressed in nasal goblet and ciliated cells within human airways. arXiv preprint arXiv:2003.06122, (2020).

L. S. Politi, E. Salsano, M. Grimaldi, Magnetic Resonance Imaging Alteration of the Brain in a Patient With Coronavirus Disease 2019 (COVID-19) and Anosmia. JAMA Neurology, (2020).

L. He et al., Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 implications for microvascular inflammation and hypercoagulopathy in COVID-19 patients. bioRxiv,088500 (2020). doi:10.1101/2020.05.11.088500

T. Coolen et al., Early postmortem brain MRI findings in COVID-19 non-survivors. medRxiv, 20090316 8 May 2020.

R. Ueha et al., Background mechanisms of olfactory dysfunction in COVID-19: expression of ACE2, TMPRSS2, and Furin in the nose and olfactory bulb in human and mice. bioRxiv, 097352 15 May 2020.

R. Chen et al., The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in human and mouse brain. bioRxiv, 030650 9 April 2020.

K. Wang et al., SARS-CoV-2 invades host cells via a novel route: CD147-spike protein. bioRxiv 988345. 14 March 2020.

S. P. Sajuthi et al., Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium. bioRxiv, 034454 10 April 2020.

L. Fodoulian et al., SARS-CoV-2 receptor and entry genes are expressed by sustentacular cells in the human olfactory neuroepithelium. bioRxiv 013268 2 April 2020.

M. Chen et al., Elevated ACE2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication. bioRxiv.084996 9 May 2020.

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Non-neuronal expression of SARS-CoV-2 entry genes in the olfactory system suggests mechanisms underlying COVID-19-associated anosmia - Science...

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This article was reviewed by Alvin Luk, PhD, MBA, CCRA

Results from two investigator-initiated studies demonstrate that a single intravitreal injection of rAAV2-ND4 (Neurophth Therapeutics Inc.) is associated with long-term safety and durable efficacy for improving vision in patients with Leber hereditary optic neuropathy (LHON), according to Alvin Luk, PhD, MBA, CCRA.

The research is comprised of a single center study including 9 patients followed for 75 to 90 months and a multicenter, international trial including 159 patients followed for up to 12 months, with observation ongoing.

Related: TANGO: Helping target genes produce more protein

Across the entire cohort, there were no serious or severe adverse events, and efficacy data showed that a majority of patients benefited with significant and sustained improvement in BCVA.

LHON is a rare inherited visual disorder that leads to bilateral vision loss and for which there is currently no effective treatment, said Luk. These 2 studies contain the largest and longest follow-up of patients treated withthis gene therapy. Based on the results, we are very excited about its potential impact for restoring vision and greater independence for patients with LHON.

Luk, the CEO at Neurophth Therapeutics Inc., noted gene therapy also is offering a positive impact on treatment.

The gene therapy restores function of the mitochondrial respiratory chain in retinal ganglion cells by delivering the NADH ubiquinone oxidoreductase subunit 4 (ND4) gene.

A series of preclinical studies confirmed that the intravitreal treatment resulted in targeted gene delivery and provided evidence of its safety.

Related: Gene therapy zeroes in as LHON treatment

Importantly, the confocal microscopy analysis confirms that rAAV2-ND4 reaches the targeted areas in the eyes where the pathological changes of LHON occur, Luk said. Therefore, providing support to the hypothesis that treatment with rAAV2-ND4 may alleviate the underlying cause of the vision loss in patients with LHON.

The clinical studies of rAAV2-ND4 gene therapy reported by Luk have been led by Bin Li, MD, PhD, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.

The first study was initiated in 2011. Known as SEE4 LHON (NCT01267422), it included 3 patients aged younger than 12 years who received 0.5 x 1010 vector genome (vg)/eye and six patients aged older than 12 years who were treated with a dose of 1.0 x 1010vg/eye.

According to investigators, the injections were given into 1 eye in an outpatient procedure and had a volume of 0.05 mL.

Although planned follow-up was initially for 12 months, 8 of the 9 patients have continued follow-up until today, Luk said.

Related: Study targets ocular damage from chronic intravitreal injections

According to Luk, there have been no late toxicities noted nor any abnormalities in intraocular pressure (IOP) in extensive laboratory testing, which includes assessments of hepatic, renal, and immune function.

Efficacy is being evaluated with measurement of the logarithm of the minimum angle of resolution (logMAR) in best-corrected visual acuity (BCVA).

Luk pointed out that at 3 months post-injection, 8 patients (89%) demonstrated improvement from baseline, and 6 of 9 patients (67%) maintained improvement at 3 years.

They also noted that the BCVA response was maintained at month 70 by 5 of the 6 responders who achieved a mean BCVA gain of 0.68 logMAR.

Patients in this study also benefited with some improvement in the untreated eye, Luk said. This kind of bilateral response was also seen in the second larger trial of this therapy and is consistent with observations by other groups working on gene therapy for this inherited eye disease.

Based on the encouraging results of SEE4LHON, a larger scale study named 4-HOPE was launched in 2017.

Related: Research targets precision dosing for gene, cell therapy

All patients were treated at three investigational sites in China and 10 patients are continuing follow-up at their local centers in Argentina.

Luk pointed out that the study enrolled 159 patients aged 6 years or older who received a unilateral injection with 1.0 x 1010 vg/eye.

The safety review showed there were no drug-related adverse events. Ocular hypertension was the most common adverse event that patients experienced, but it is related to the course of oral steroid treatment that is given in conjunction with the injection, Luk explained.

The IOP elevations are generally mild and resolve spontaneously once the steroid treatment is ended, he said.

Of the 159 enrolled patients, 106 had data available from a 12-month follow-up visit. Of the 106 patients, Luk noted that 63% showed an improvement from baseline BCVA with an average gain of 0.3 logMAR.

Related: Greater IOP-lowering with iStent inject

It is important to point out that the patients enrolled in this study represent a heterogenous group with a wide range of ages, time since diagnosis, and baseline BCVA values, Luk concluded. We would not be surprised to see even better efficacy results in a cohort enrolled using narrower inclusion criteria.

Luk noted some of the patients in the study also benefited with bilateral BCVA improvement.

Taking improvements ofinjected and noninjected eyes into consideration from baseline to 12 months post treatment, 43.7% patients who classified as legally blind by World Health Organizationcriteria ( > 1.3 logMAR) were recovered to low (> 0.5 to 1.3 logMAR) or normal ( 0.5 logMAR) vision.Read more by Lynda Charters

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Alvin Luk, PhD, MBA, CCRAe:alvin.luk@neuropth.comLuk is an employee of Neurophth Therapeutics Inc, but has no other relevant financial interests to disclose.

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Research shows promising results for LHON gene therapy - Ophthalmology Times

Recommendation and review posted by Bethany Smith

DALLAS--(BUSINESS WIRE)--Taysha Gene Therapies, a patient-centric gene therapy company with a mission to eradicate monogenic CNS disease, today announced that it has closed an oversubscribed $95 million Series B financing with a premier syndicate of life science investors, led by Fidelity Management & Research Company LLC. Additional new investors include funds and accounts managed by BlackRock, GV (formerly Google Ventures), Invus, Casdin Capital, Franklin Templeton, Octagon Capital, Perceptive Advisors LLC, Sands Capital, ArrowMark Partners and Venrock Healthcare Capital Partners. Also participating in the round were founding investors PBM Capital and Nolan Capital. Proceeds from the Series B financing will be used to advance the initial cohort of lead programs into the clinic, accelerate progress on anticipated IND submissions, build a commercially scalable GMP manufacturing facility and continue development of the companys extensive portfolio of potentially curative gene therapies in partnership with the UT Southwestern Gene Therapy Program.

This significant investment from premier, long-term investors will allow us to advance our mission of eradicating monogenic CNS disease for the thousands of patients who suffer from these devastating disorders, said RA Session II, President, CEO and Founder of Taysha. We remain on track and expect to file four Investigational New Drug (IND) applications by the end of 2021, with TSHA-101 initiating clinical studies later this year for the treatment of GM2 Gangliosidosis.

Taysha is currently developing a deep and sustainable pipeline of 17 gene therapy product candidates, with exclusive options to acquire four additional programs across three distinct franchises, including neurodegenerative diseases, neurodevelopmental disorders and genetic forms of epilepsy. TSHA-101 is expected to initiate clinical studies later this year for the treatment of GM2 Gangliosidosis, followed by TSHA-102 for the treatment of Rett syndrome, TSHA-103 for the treatment of SLC6A1 haploinsufficiency disorder and TSHA-104 for the treatment of SURF1 deficiency. Taysha expects to file INDs for each of these four product candidates by the end of 2021.

We have brought together experts in gene therapy with leading healthcare and institutional investors to create a company that is uniquely positioned to advance the development of potentially curative gene therapies for CNS disease in rare and large patient populations, said Sean Nolan, Chairman of the Board of Taysha. We believe this financing provides significant validation of our corporate strategy and will enable us to continue to rapidly translate programs from preclinical development into the clinic.

About Taysha Gene Therapies

Taysha Gene Therapies is a patient-centric gene therapy company with a mission to eradicate monogenic CNS disease. We are focused on developing and commercializing AAV-based gene therapies for the treatment of monogenic diseases of the CNS in both rare and large patient populations. We were founded in partnership with The University of Texas Southwestern Medical Center, or UT Southwestern, to develop and commercialize transformative gene therapy treatments. Together with UT Southwestern, we are advancing a deep and sustainable product portfolio of 17 gene therapy product candidates, with exclusive options to acquire four additional development programs. By combining our management teams proven experience in gene therapy drug development and commercialization with UT Southwesterns world-class gene therapy research capabilities, we believe we have created a powerful engine to develop transformative therapies to dramatically improve patients lives. More information is available at http://www.tayshagtx.com.

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Taysha Gene Therapies Announces Oversubscribed $95 Million Series B Financing to Bolster Initial Clinical Studies in GM2 Gangliosidosis and Advance...

Recommendation and review posted by Bethany Smith

DUBLIN--(BUSINESS WIRE)--The "Competitive Landscape Analysis of Recent Cell and Gene Therapy Innovations" report has been added to ResearchAndMarkets.com's offering.

This research identifies some of the key developments across CAR-T cell therapies and provides insights across technological, IP, and investment landscapes. The study also provides an analysis of the competitive landscape while highlighting the key growth opportunities within the CAR-T cell therapy platform.

Companies Mentioned

Key Topics Covered:

1.0 Executive Summary

1.1 Research Focus: Emerging Technologies Enabling chimeric antigen receptor (CAR) T-cell Therapies

1.2 Analysis Framework: The Author's Core Value

1.3 Research Methodology: Five Steps Toward Success

1.4 Key Findings of Technology Breakthrough Driving Sepsis Diagnosis

2.0 Technology Snapshot

2.1 Rising Pace of Cell and Gene Therapy Approvals

2.2 Regulatory and Ethical Perspectives on Gene Therapy

2.3 Rising Demand for Precision Medicine Strategies

2.4 Manufacturing Continues to be the Key Bottle Neck

2.5 II Generation Chimeric Antigen ReceptorS Likely to Dominate the Cell Therapy Landscape in the Future

2.6 CD-19 is the Most Common Target Antigen for Allogeneic CAR-T Therapies

3.0 Emerging Patent Landscape

3.1 Steady Increase in Patent Grants for CAR-T Cell Therapies

3.2 University of Pennsylvania and Novartis Lead the Patent Landscape for CAR-T Cell Therapies

3.3 China and the US Lead the Patent Landscape for CAR-T Cell Therapies

3.4 Snapshot of Key Patent Grants: Novartis

3.5 Snapshot of Key Patent Grants: Cellectis and BlueBird Bio

4.0 Analysis of the Investment Landscape

4.1 Key M&A Trends Across the Global Life Sciences Sector

4.2 Gene Therapy - Venture Capital Funding Assessment

4.3 Gene Therapy - Big Pharma In-licensing Deals Assessment

4.4 Strategic Insights: Cell Therapies and Gene Therapies, Viral Vector CMOS

5. Analysis of the Competitive Landscape

5.1 Allogene Therapeutics

5.2 Precision BioSciences Inc.

5.3 CRISPR Therapeutics AG

5.4 Cellectis S.A.

5.5 Celyad

5.6 Bristol-Myers Squibb (BMS)

5.7 Gilead

5.8 Novartis

5.9 BlueBird Bio

5.10 Summary of the Scoring Methodology

5.11 Competitive Analysis of CAR-T Participants

6.0 CAR-T Cell Therapies: Growth Opportunity Universe

6.1 Growth Opportunity: CAR-T for Solid tumors, 2020

7.0 Industry Influencers

7.1 Key Contacts

7.2 Legal Disclaimer

For more information about this report visit https://www.researchandmarkets.com/r/ndt6sc.

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2020 Competitive Landscape Analysis of Recent Cell and Gene Therapy Innovations - ResearchAndMarkets.com - Business Wire

Recommendation and review posted by Bethany Smith

Researchstore.bizhas published the latest research study onGlobal Gene Therapy in Oncology Market 2020 by Company, Type and Application, Forecast to 2025that presents a complete overview of the market with a detailed description of the global market. The report provides complete information about the advancing market trade and business data. The report highlights the dynamics of the market such as internal and external driving forces, restraining factors, risks, challenges, threats, and opportunities. The complete view linked with the progress of this globalGene Therapy in Oncologymarket by the significant players involved in this business. Analysts of this research report predict the financial attributes such as investment, pricing structures along with the profit margin.

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The report delivers brief information on the competitors and the specific growth opportunities with key market drivers. Complete market analysis is given by segmenting the report by companies, region, type, and applications in the report. Top players also analyzed by splitting the globalGene Therapy in Oncologymarket by product type and applications/end industries. The overall report encompasses many aspects of the industry like market size, market status, market trends, and forecast. Additionally, development trends, competitive landscape analysis, and key regions development status has been demonstrated. It also focuses on a product analysis, application analysis, competitive strategies, and strategies impacting the industry. An expert and in-depth analysis of key business trends and future market development prospects, key drivers and restraints, profiles of major market players, and forecasting for 2020 to 2025 time-period has been given.

The report covers the manufacturers data, including shipment, price, revenue, gross profit, interview record, business distribution. With mergers and acquisitions and fast building of product portfolio, key players in the globalGene Therapy in Oncologymarket are analyzed to take charge of a leading share. Some of the tough competitors in the global market areBristol-Myers Squibb, Editas Medicine, Amgen, Cold Genesys, CRISPR Therapeutics, Advantagene, Idera Pharmaceuticals, Bio-Path Holdings, AstraZeneca, Geron Corp, Mologen AG, Oncotelic, Intellia Therapeutics, Sillajen Biotherapeutics, Oncolytics Biotech, Merck, Johnson & Johnson, Shenzhen SiBiono GeneTech, Oncosec, Marsala Biotech, Tocagen, UniQure, Ziopharm Oncology.

Geographically, this market report studies the following key geographical regions:North America (United States, Canada and Mexico), Europe (Germany, France, United Kingdom, Russia and Italy), Asia-Pacific (China, Japan, Korea, India, Southeast Asia and Australia), South America (Brazil, Argentina), Middle East & Africa (Saudi Arabia, UAE, Egypt and South Africa)

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Table of Contents:1 Market Overview2 Company Profiles3 Market Competition, by Players4 North America Market Size and Forecast by Countries5 Europe Market Size and Forecast by Countries6 Asia-Pacific Market Size and Forecast by Countries7 South America Market Size and Forecast by Countries8 Middle East & Africa Market Size and Forecast by Countries9 Market Size Segment by Type10 Market Size Segment by Application11 Research Findings and Conclusion12 Appendix

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Global Gene Therapy in Oncology Market 2020 Growth Statistics, New Opportunities, Competitive Outloo - PharmiWeb.com

Recommendation and review posted by Bethany Smith

Aug. 4, 2020 06:00 UTC

LONDON--(BUSINESS WIRE)-- Gyroscope Therapeutics Limited, a clinical-stage retinal gene therapy company, today announced the appointment of leading experts in retinal disease, gene therapy and the complement system to its Clinical and Scientific Advisory Boards. The newly appointed boards will help guide the development of the company's lead investigational gene therapy, GT005, a one-time therapy being developed to potentially slow the progression of dry age-related macular degeneration (AMD), as well as novel gene therapy delivery systems and additional pipeline candidates.

This is an exciting time for Gyroscope and we are honoured to have a group of highly esteemed leaders in retinal surgery, ophthalmology and gene therapy join our Clinical Advisory Board, said Nadia Waheed, M.D., Chief Medical Officer of Gyroscope. We look forward to working with these leaders as we advance the clinical development of GT005 and our proprietary delivery system, with the ultimate goal of helping preserve the sight of millions of people who suffer from vision loss as a result of dry AMD.

We have embarked upon an ambitious journey exploring the potential of gene therapy beyond rare disease and building a pipeline of potential medicines for one of the worlds leading causes of blindness, said Jane Hughes, Ph.D., Chief Scientific Officer of Gyroscope. We are excited to welcome our Scientific Advisory Board members to Gyroscope and to benefit from the insights of some of the worlds leading experts as we advance our understanding of the role of the complement system in retinal diseases.

Members of the Gyroscope Therapeutics Clinical Advisory Board include:

Professor Jacque Duncan, M.D. Professor of Ophthalmology at the University of California, San Francisco School of Medicine.

Jeffrey Heier, M.D. Co-President and Medical Director, Director of the Vitreoretinal Service and Director of Retina Research at Ophthalmic Consultants of Boston.

Professor Allen Ho, M.D. Professor of Ophthalmology at Sidney Kimmel Medical College of Thomas Jefferson University, and Attending Surgeon and Director of Retina Research at Wills Eye Hospital in Philadelphia.

Professor Nancy Holekamp, M.D. Director of Retina Services at Pepose Vision Institute and Professor of Clinical Ophthalmology at the Washington University School of Medicine in St. Louis.

Arshad Khanani, M.D., M.A. Managing Partner, Director of Clinical Research and Director of Fellowship at Sierra Eye Associates, and Clinical Associate Professor at the University of Nevada, Reno School of Medicine.

Professor Robert MacLaren Professor of Ophthalmology at the University of Oxford in the United Kingdom, Consultant Ophthalmologist at the Oxford Eye Hospital, Honorary Professor of Ophthalmology at the UCL Institute of Ophthalmology, Honorary Consultant Vitreoretinal Surgeon at Moorfields Eye Hospital, and an NIHR Senior Investigator. Professor MacLaren is also a member of the Scientific Advisory Board.

Professor Sir Keith Peters, M.D. Senior Consultant to The Francis Crick Institute in London and Regius Professor of Physic Emeritus at the University of Cambridge in the United Kingdom. Professor Peters is also a member of the Scientific Advisory Board.

Professor Hendrik Scholl, M.D. Founder and Director of the Institute of Molecular and Clinical Ophthalmology Basel in Switzerland, and Professor and Chairman of the Department of Ophthalmology at the University of Basel.

Professor David Steel, M.D., MBBS, FRCOphth Consultant Ophthalmologist at Sunderland Eye Infirmary in the United Kingdom and Honorary Professor of Retinal Surgery at Newcastle University in Newcastle upon Tyne, United Kingdom. Professor Steel is also a member of the Scientific Advisory Board.

Professor Bernhard Weber, Ph.D. Head of Institute of Human Genetics, Head of Institute of Clinical Human Genetics, and Director of the Diagnostics Unit for DNA Testing and Vice President of Research of the University of Regensburg, Germany.

Charles Wykoff, M.D., Ph.D. Director of Research at Retina Consultants of Houston, Deputy Chair for Ophthalmology at Blanton Eye Institute, and Clinical Associate Professor of Ophthalmology Weill Cornell Medical College at Houston Methodist Hospital.

Members of the Gyroscope Scientific Advisory Board include:

Professor Alberto Auricchio, M.D. Professor of Medical Genetics at the Department of Advanced Biomedicine, Federico II University in Naples, and Coordinator of the Molecular Therapy Program at Telethon Institute of Genetics and Medicine (TIGEM) in Pozzuoli (NA), in Italy.

Professor Pete Coffey, DPhil Theme Lead of Development, Ageing and Disease at University College Londons Institute of Ophthalmology and the Co-Executive Director of Translation at the University of California Santa Barbaras Center for Stem Cell Biology and Engineering.

Professor Claire Harris Professor of Molecular Immunology at Newcastle University.

Professor David Kavanagh, Ph.D., FRCP Professor of Complement Therapeutics at the National Renal Complement Therapeutics Centre (NRCTC), Newcastle University.

Professor Sir Peter Lachmann, FRS, FMEDSCI Emeritus Sheila Joan Smith Professor of Immunology, University of Cambridge.

Professor Robert MacLaren Professor MacLaren is also a member of the Clinical Advisory Board.

Professor Sir Keith Peters, M.D. Professor Peters is also a member of the Clinical Advisory Board.

Professor Matthew Pickering, Ph.D., M.B., B.S. Professor of Rheumatology, Imperial College LondonHonorary Consultant Rheumatologist, Imperial College Healthcare NHS Trust, and Wellcome Trust Senior Fellow in Clinical Science.

Professor David Steel, M.D., MBBS, FRCOphth Professor Steel is also a member of the Clinical Advisory Board.

Professor Timothy Stout, M.D. Sid W. Richardson Professor and Margarett Root Brown Chair of the Department of Ophthalmology, and Director of the Cullen Eye Institute at Baylor College of Medicine in Houston.

Full biographies for members of the Gyroscope Advisory Boards are available at http://www.gyroscopetx.com.

About Gyroscope Therapeutics: Vision for Life

Gyroscope Therapeutics is a clinical-stage retinal gene therapy company developing and delivering gene therapy beyond rare disease to treat a leading cause of blindness, dry age-related macular degeneration (AMD). Currently, there are no approved treatments for dry AMD.

Our investigational gene therapy, GT005, is designed to restore balance to a part of our immune system called the complement system. An overactive complement system leads to inflammation that damages healthy eye tissues. Our ultimate goal is to slow the progression of dry AMD. Patients in our Phase I/II clinical trial, known as the FOCUS study, receive a single dose of GT005 through an injection under their retina.

Syncona Ltd, our lead investor, helped us create the only retinal gene therapy company to combine discovery, research, drug development, a manufacturing platform, and surgical delivery capabilities. Headquartered in London with locations in Philadelphia and San Francisco, our mission is to preserve sight and fight the devastating impact of blindness. For more information, visit http://www.gyroscopetx.com and follow us on Twitter (@GyroscopeTx) and on LinkedIn.

View source version on businesswire.com: https://www.businesswire.com/news/home/20200803005822/en/

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Gyroscope Announces Appointment of Leaders in Retinal Disease, Gene Therapy and the Complement System to Its Clinical and Scientific Advisory Boards -...

Recommendation and review posted by Bethany Smith

Norman Swan: Alzheimer's disease is the commonest form of dementia, and the results of billions of dollars of research investment have been bitterly disappointing in terms of finding an effective treatment. However, experiments on mice by a group from the Dementia Research Centre at Macquarie University have come up with some promising findings. Professor Lars Ittner is the director of the centre. Welcome to the Health Report Lars.

Lars Ittner: Hello, how are you?

Norman Swan: Now, essentially you are targeting an enzyme which protects nerve cells in the brain from the toxic effects of amyloid beta and that's one of the two main substances which accumulate in Alzheimer's disease. What did you actually do in this study?

Lars Ittner: So in this we found prior to this study that this enzyme activity that protects the brain from Alzheimer's disease is actually lost in Alzheimer's disease. And we devised a gene therapy to replace the enzyme activity and bring the enzyme back into the brain cells.

Norman Swan: And these are mice which replicate Alzheimer's disease in some shape or form.

Lars Ittner: Yes, they are, so we genetically engineered them to develop Alzheimer's disease.

Norman Swan: And they were showing signs of memory and thinking problems?

Lars Ittner: Yes, so their ability to form memory and then store the memory over longer terms is compromised.

Norman Swan: And this was the gene for this enzyme?

Lars Ittner: So we brought backit's called the P38 gamma gene, which we brought back into the brains of these mice and that restored their ability to form memory.

Norman Swan: So you actually got healing?

Lars Ittner: So we were quite surprised because when you set out with these type of studies you expect at most that you stop the progression. But yes, we got far more than we set out for.

Norman Swan: People have tried gene therapy before from Parkinson's disease and other things, and it's quite hard to get the gene therapy into the brain. And of course Alzheimer's disease is quite widespread as opposed to Parkinson's disease. How do you get the gene therapy in reliably?

Lars Ittner: So from the early days of gene therapy done in Parkinson's disease, the vehicles that are used to bring the genes into organisms or in the brain in particular have improved, so these days we use modified viruses that we take advantage of their ability to infect brain cells, and they then deliver the genes for us.

Norman Swan: In the right place. Were there any side effects?

Lars Ittner: So we did toxicity studies as part of our study, and then you use incredibly high amounts of the virus, and we did not see long-term side-effects.

Norman Swan: How do you getthere's something called the bloodbrain barrier, the brain is a protected organ and it's quite hard for things to get into the brain because of this barrier, how did you get beyond that with these gene therapies?

Lars Ittner: So with the mice we can take advantage of a modified virus which has been selected to actually passage this naturally, but in humans you would do a single injection, it's like a lumbar puncture, it's at the base of your neck, and it's directly into the liquid around the brain, so you basically mechanically bypass the bloodbrain barrier.

Norman Swan: There have been very disappointing results. I mean, what happens in mice particularly in Alzheimer's disease does not necessarily happen in humans, and there's not a single amyloid beta therapy that has had much effect on the brains of the people with Alzheimer's disease. Why do you think this one might work in humans when others haven't?

Lars Ittner: So the problem with the amyloid beta is that it is now understood that this is a disease inducing pathology but is not required for the progression of the disease, and we are targeting here actually the tau protein specifically which is

Norman Swan: It's the other thing that

Lars Ittner: Exactly, and that is responsible for the progression of the disease, so it's actually moving away from the amyloid beta as a drug target which has failed in the past.

Norman Swan: Now, with COVID-19 around we are getting used to the language of clinical trials and accelerating trials. When are you ready to go to phase 1 which would be a safety trial in humans?

Lars Ittner: So preclinical experiments have actually been completed for this particular study, and the next step are in fact phase 1 clinical trials, and we are currently working with Macquarie University and their commercialisation arm to find the right partner to move forward into clinical trials.

Norman Swan: Fascinating. Well, we'll follow that up when you do. Thanks for joining us.

Lars Ittner: It was my pleasure.

Norman Swan: Professor Lars Ittner is director of the Dementia Research Centre at Macquarie University.

You've been listening to the Health Report, I'm Norman Swan, and I'd really enjoy your company next week.

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Of mice and memories: Gene therapy study returns function in Alzheimer's mice - ABC News

Recommendation and review posted by Bethany Smith

BRISBANE, Calif.--(BUSINESS WIRE)--Sangamo Therapeutics, Inc. (Nasdaq: SGMO), a genomic medicine company, today reported second quarter 2020 financial results and recent business highlights.

We are very excited about our global collaboration agreement announced with Novartis last week. This is our second impactful partnership announced this year, and we believe it affirms the value our industry sees in our zinc finger technology, said Sandy Macrae, CEO of Sangamo. By advancing our robust partnership strategy, we proactively expand our genomic medicines pipeline into potential additional new indications, create substantial value for shareholders, and advance our mission to bring our medicines to patients.

Recent Highlights

Second Quarter 2020 Financial Results

Cash, cash equivalents and marketable securities were $664.9 million as of June 30, 2020, compared to $384.3 million as of December 31, 2019. The balance at the end of the second quarter reflects amounts received from our previously announced collaboration with Biogen for an upfront license fee and issuance of Sangamo common stock.

Consolidated net loss attributable to Sangamo for the second quarter ended June 30, 2020 was $35.9 million, or $0.26 per share, compared to a net loss of $30.3 million, or $0.26 per share, for the same period in 2019. Revenues for the second quarter ended June 30, 2020 were $21.6 million, compared to $17.5 million for the same period in 2019.

Three Months Ended June 30,

Six Months Ended June 30,

2020

2019

2020

2019

$

41.5

$

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$

83.0

$

71.3

17.9

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59.4

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$

52.7

$

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$

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Total operating expenses were $59.4 million for the second quarter ended June 30, 2020, compared to $51.1 million for the same period in 2019. Non-GAAP operating expenses, which exclude stock-based compensation expense, were $52.7 million for the second quarter ended June 30, 2020, compared to $46.2 million for the same period in 2019. The increase in operating expenses reflects our headcount growth and facilities expansion to support the advancement of our therapeutic pipeline and manufacturing capabilities. These increases were partially offset by a decrease in clinical and manufacturing supply expenses.

Financial Guidance for 2020

Conference Call

Sangamo will host a conference call today, August 5, 2020, at 5:00 p.m. Eastern Time, which will be open to the public. The call will also be webcast live and can be accessed via a link on the Sangamo Therapeutics website in the Investors and Media section under Events and Presentations.

The conference call dial-in numbers are (877) 377-7553 for domestic callers and (678) 894-3968 for international callers. The conference ID number for the call is 5667347. Participants may access the live webcast via a link on the Sangamo Therapeutics website in the Investors and Media section under Events and Presentations. A conference call replay will be available for one week following the conference call. The conference call replay numbers for domestic and international callers are (855) 859-2056 and (404) 537-3406, respectively. The conference ID number for the replay is 5667347.

About Sangamo Therapeutics

Sangamo Therapeutics is committed to translating ground-breaking science into genomic medicines with the potential to transform patients lives using gene therapy, ex vivo gene-edited cell therapy, and in vivo genome editing and genome regulation. For more information about Sangamo, visit http://www.sangamo.com.

Forward-Looking Statements

This press release contains forward-looking statements regarding Sangamos current expectations. These forward-looking statements include, without limitation, statements relating to the potential to develop, obtain regulatory approvals for and commercialize therapies to treat certain diseases and the timing, availability and costs of such therapies, the potential to use our zinc finger technology to develop such therapies, the potential to receive an upfront licensing fee and earn milestone payments and royalties under the collaboration with Novartis and the timing of such fees, payments and royalties, the anticipated benefits of Sangamos organizational changes, Sangamos financial resources and expectations, the effects of the evolving COVID-19 pandemic and the anticipated impacts of the pandemic on the business and operations of Sangamo and its collaborators, Sangamos 2020 financial guidance related to GAAP and non-GAAP total operating expenses and stock-based compensation and other statements that are not historical fact. These statements are not guarantees of future performance and are subject to certain risks and uncertainties that are difficult to predict. Factors that could cause actual results to differ include, but are not limited to, risks and uncertainties related to the effects of the evolving COVID-19 pandemic and the impacts of the pandemic on the global business environment, healthcare systems and business and operations of Sangamo and its collaborators; the research and development process, including the results of clinical trials; the regulatory approval process for product candidates; the manufacturing of products and product candidates; the commercialization of approved products; the potential for technological developments that obviate technologies used by Sangamo and its collaborators; the potential for Sangamo or its collaborators to breach or terminate collaboration agreements; the potential for Sangamo to fail to realize its expected benefits of its collaborations; and Sangamos ability to achieve expected future financial performance.

There can be no assurance that Sangamo and its collaborators will be able to develop commercially viable products. Actual results may differ from those projected in forward-looking statements due to risks and uncertainties that exist in the operations and business environments of Sangamo and its collaborators. These risks and uncertainties are described more fully in Sangamos Securities and Exchange Commission filings and reports, including in Sangamos Quarterly Report on Form 10-Q for the quarter ended June 30, 2020. Forward-looking statements contained in this announcement are made as of this date, and Sangamo undertakes no duty to update such information except as required under applicable law.

Non-GAAP Financial Measures

To supplement Sangamos financial results and guidance presented in accordance with GAAP, Sangamo presents non-GAAP total operating expenses, which exclude stock-based compensation expense from GAAP total operating expenses. Sangamo believes that this non-GAAP financial measure, when considered together with its financial information prepared in accordance with GAAP, can enhance investors and analysts ability to meaningfully compare Sangamos results from period to period and to its forward-looking guidance, and to identify operating trends in Sangamos business. Sangamo has excluded stock-based compensation expense because it is a non-cash expense that may vary significantly from period to period as a result of changes not directly or immediately related to the operational performance for the periods presented. This non-GAAP financial measure is in addition to, not a substitute for, or superior to, measures of financial performance prepared in accordance with GAAP. Sangamo encourages investors to carefully consider its results under GAAP, as well as its supplemental non-GAAP financial information, to more fully understand Sangamos business.

Three months ended

Six Months Ended

June 30,

June 30,

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2019

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$

21,553

Original post:
Sangamo Therapeutics Reports Business Highlights and Second Quarter 2020 Financial Results - Business Wire

Recommendation and review posted by Bethany Smith

Global Gene Therapy Market report forecast to 2026 investigate the Impact of COVID-19 on Industry further market size, manufactures, types, applications and key regions like North America, Europe, Asia Pacific, Central & South America and Middle East & Africa, focuses on the consumption of Gene Therapy in these regions. This report also studies the global Gene Therapy market share, competition landscape, status share, growth rate, future trends, market drivers, opportunities and challenges, sales channels and distributors.

COVID-19 can affect the global economy in 3 main ways: by directly affecting production and demand, by creating supply chain and market disturbance, and by its financial impact on firms and financial markets.

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Leading Players from the market are covered in this report- Sangamo, Spark Therapeutics, Dimension Therapeutics, Avalanche Bio, Celladon

Impact of Covid-19 on Gene Therapy Industry 2020

Gene Therapy Market report analyses the impact of Coronavirus (COVID-19) on the Gene Therapy industry. Since the COVID-19 virus outbreak in December 2019, the disease has spread to almost 180+ countries around the globe with the World Health Organization declaring it a public health emergency. The global impacts of the coronavirus disease 2019 (COVID-19) are already starting to be felt, and will significantly affect the Gene Therapy market in 2020.

The outbreak of COVID-19 has brought effects on many aspects, like flight cancellations; travel bans and quarantines; restaurants closed; all indoor events restricted; emergency declared in many countries; massive slowing of the supply chain; stock market unpredictability; falling business assurance, growing panic among the population, and uncertainty about future.

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Market Segments:

Based on Types, the Gene Therapy Market is Classsified as Ex vivo, In vivo

Based on Application, this report focuses on the status and outlook for major applications/end users, consumption (sales), market share and growth rate for each application, including Cancer Diseases, Monogenic Diseases, Infectious Diseases, Cardiovascular Diseases, Others

Gene Therapy Market Report Provides Comprehensive Analysis as Following:

Study on Table of Contents:

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Detailed Information on Gene Therapy Market 2020 | Covid-19 Impact Analysis | Sangamo, Spark Therapeutics, Dimension Therapeutics, Avalanche Bio,...

Recommendation and review posted by Bethany Smith

Cell and gene therapies offer some of the most groundbreaking advancements in patient care the pharma industry has ever seen. However, to fully realise the potential of these innovative therapies, integration across the supply chain is critical particularly with reimbursement and logistics.

As of the end of 2019, there were 17 cell and gene therapy products approved by the FDA. Now, there is more momentum than ever to bring these innovative medicines to market, and the FDA anticipates that it will approve 10 to 20 cell and gene therapy products a year within the next five years.

These therapies can offer new opportunities to patients with conditions where there are few treatment options and no cures. But the potential these products offer could remain largely unrealised if manufacturers and their partners are not prepared. Cell and gene therapy innovators and other stakeholders across the supply chain need to set themselves up for the greatest chance of success by addressing three key challenges: access barriers; logistics; and the need for stakeholder education.

Addressing access barriers through innovative payment models

While cell and gene therapies offer novel treatment to patients who have limited options, the cost associated with each product anywhere between $375,000 and $2 million can create significant access barriers. This challenge is compounded compared to traditional treatments that typically require multiple doses, as many cell and gene therapies are one-time treatments.

This situation increases the risk for payers covering the cell and gene therapy, given that the long-term magnitude and durability of the product is not known at the time of first regulatory approval and patients switch insurance carriers throughout their lifetimes.

Stakeholders across the industry have recognised the increasing need to consider alternatives to the standard payment system if cell and gene therapies are to become widely available

Stakeholders across the industry, such as manufacturers and payers, have recognised the increasing need to consider alternatives to the standard payment system if cell and gene therapies are to become widely available. As a result, a variety of payment models have been discussed:

We have already begun to see payers and manufacturers of cell and gene therapies attempt to adopt alternative payment models for their products, and more should continue to do so as additional therapies come through the approval pipeline. With a range of interdependencies that affect the success of cell and gene therapies, manufacturers need to develop their reimbursement strategy early in the commercialisation process. Its critical for manufacturers to consider various payment models for cell and gene therapies ahead of approvals so that they can maximise patient access for their products.

Ensuring therapies reach their patients

Manufacturers have noted that the delivery of critical shipments is one of the biggest challenges facing the advanced therapy industry, as if you cannot connect cell and gene therapies with patients their efficacy is irrelevant. The inclusion of patients into the cell and gene therapy supply chain, the potentially life-altering impact of the therapies and their high cost leaves no room for failure.

These therapies require timely delivery and maintaining precise temperature control is integral for the patient and the product. It calls for near-perfect execution ranging from mapping the best transportation route and planning for multiple contingencies (such as closed international borders), to how the packaging itself is evaluated, validated and used to maintain product integrity in all conditions.

Successful execution of these processes requires both manufacturers and other supply chain partners to maintain a robust logistics platform. Currently, many manufacturers are developing different logistics plans for each of the stages of a clinical trial, only to find out these processes dont scale when it is time to commercialise. Developing a plan early that can scale will position a product for success as more therapies are reviewed and approved. Manufacturers need to work with their 3PL and distribution partners to ensure control and oversight throughout the product journey to the patient failure to do so will put patient outcomes and commercial success at risk.

Promoting stakeholder education

Many stakeholders spanning payers, providers and patients do not understand the full clinical, logistical, operational, financial or reimbursement components associated with cell and gene therapies. Manufacturers can leverage the preliminary data theyve gathered throughout their initial commercialisation journey to support education and awareness efforts with these key stakeholders.

As payers conduct product reviews earlier and earlier in the development lifecycle, their demand for pre-approval information continues to grow. However, recent research shows that a gap still exists between the evidence sought by healthcare decision makers and what is being shared by manufacturers. COVID-19 has also caused delays in providing information in a timely and relevant manner, causing even more challenges for stakeholders.

The use of Pre-approval Information Exchange (PIE) is one way to combat these challenges. PIE allows manufacturers to communicate ahead of approval to partners with accurate, and unbiased information on products or indications, and share information early that may result in a place saved at the table for their product. This information equips stakeholders with the education needed to understand a products value story and positioning. Partners embedded in the industry particularly those with a patient-centric focus can also offer manufacturers the information they need to showcase the value of these products to patients.

The cell and gene therapy space is continuing to evolve. Through analysing payment models, working with partners to navigate logistical challenges and leveraging data, patients will have more opportunities than ever to access the next generation of medicines. Overall, the collaboration between stakeholders across the supply chain will facilitate a world in which we see 10 to 20 cell and gene therapies not only approved each year but out in the market directly impacting patients.

About the authors

Alex Guite is vice president services and alliances at World Courier. As strategy and services lead, Alex is responsible for developing and executing key strategic initiatives.Before joining World Courier in 2013 as head of pricing, Alex spent nearly 3 years with Oliver Wyman as a consultant in the Health and Life Sciences practice.

Ana Stojanovska is vice president, reimbursement & policy insights at Xcenda. She has extensive practical knowledge in working with key stakeholders to motivate local coverage of new products by both public and private payers and providing strategic compendia analyses and ongoing coding support. Prior to Xcenda, Ana worked for a bipartisan, non-profit health policy organization in Washington DC, where she helped lead research, health policy analysis, media outreach, and fundraising.

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Preparing for an influx of cell and gene therapy approvals - - pharmaphorum

Recommendation and review posted by Bethany Smith

Global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market report provides 6 Years Forecast, including detailed Coronavirus (COVID-19) impact analysis on Market Size, Regional and Country-Level Market Size, Segmentation Market Growth, Market Share, Competitive Landscape, Sales Analysis and Value Chain Optimization. This Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing market competitive landscape offers details by topmost key manufactures (BioReliance, Richter-Helm, UniQure, Cobra Biologics, MassBiologics, Oxford BioMedica, Lonza, MolMed, FinVector, FUJIFILM Diosynth Biotechnologies, Brammer Bio, bluebird bio, Aldevron, Spark Therapeutics, VGXI, Biovian, Eurogentec, Novasep, PlasmidFactory, Cell and Gene Therapy Catapult, Vigene Biosciences) including Company Overview, Company Total Revenue (Financials), Market Potential, Presence, Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing industry Sales and Revenue Generated, Market Share, Price, Production Sites and Facilities, SWOT Analysis, Product Launch. For the period 2014-2020, this study provides the Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing sales, revenue and market share for each player covered in this report.

SDMR has recently published a report, on Global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market Insights, Forecast to 2025. The market research report is a brilliant, complete, and much-needed resource for Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing . The research report speak about the potential development openings that exist in the worldwide market. The report is broken down on the basis of research procedures procured from historical and forecast information. The global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing market is relied upon to develop generously and flourish as far as volume and incentive during the gauge time frame. The report will give a knowledge about the development openings and controls that will build the market. Pursuers can increase important perception about the eventual fate of the market.

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The prime objective of this report is to help the user understand the market in terms of its definition, segmentation, market potential, influential trends, and the challenges that the market is facing with 10 major regions and 30 major countries. Deep researches and analysis were done during the preparation of the report. The readers will find this report very helpful in understanding the market in depth. The data and the information regarding the market are taken from reliable sources such as websites, annual reports of the companies, journals, and others and were checked and validated by the industry experts. The facts and data are represented in the report using diagrams, graphs, pie charts, and other pictorial representations. This enhances the visual representation and also helps in understanding the facts much better.

The Global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market is estimated to reach xxx million USD in 2020 and projected to grow at the CAGR of xx% during the 2021-2026. The report analyses the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing market, the market size and growth, as well as the major market participants.

Segmentation by Product:

AAVAdenoviralLentiviralRetroviralPlasmid DNAOther Vectors

Segmentation by Application:

CancersInherited DisordersViral InfectionsOthers

Global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market: Competitive RivalryThe segmentation is used to decide the target market into smaller sections or segments like product type, application, and geographical regions to optimize marketing strategies, advertising techniques, and global as well as regional sales efforts of Global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market. Common characteristics are being considered for segmentation such as global market share, common interests, global demand and access control unit supply. Moreover, the report compares the production value and growth rate of the Global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing market across different geographies.While segmentation has been provided to list down various facets of the Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing market, analysis methods such as S.T.E.E.P.L.E., S.W.O.T., Regression analysis, etc. have been utilized to study the underlying factors of the market. Summarization of various aspects consisted of the report has also been encompassed.

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Key Questions Answered: What is the size and CAGR of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market? Which are the leading segments of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market? What are the key driving factors of the most profitable regional market? What is the nature of competition in the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market? How will the global Home Appliance market advance in the coming years? What are the main strategies adopted in the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market?

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Table of ContentsReport Overview: It includes major players of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market covered in the research study, research scope, and Market segments by type, market segments by application, years considered for the research study, and objectives of the report.

Global Growth Trends: This section focuses on industry trends where market drivers and top market trends are shed light upon. It also provides growth rates of key producers operating in the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market. Furthermore, it offers production and capacity analysis where marketing pricing trends, capacity, production, and production value of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market are discussed.

Market Share by Manufacturers: Here, the report provides details about revenue by manufacturers, production and capacity by manufacturers, price by manufacturers, expansion plans, mergers and acquisitions, and products, market entry dates, distribution, and market areas of key manufacturers.

Market Size by Type: This section concentrates on product type segments where production value market share, price, and production market share by product type are discussed.

Market Size by Application: Besides an overview of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market by application, it gives a study on the consumption in the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market by application.

Production by Region: Here, the production value growth rate, production growth rate, import and export, and key players of each regional market are provided.

Consumption by Region: This section provides information on the consumption in each regional market studied in the report. The consumption is discussed on the basis of country, application, and product type.

Company Profiles: Almost all leading players of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market are profiled in this section. The analysts have provided information about their recent developments in the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market, products, revenue, production, business, and company.

Market Forecast by Production: The production and production value forecasts included in this section are for the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market as well as for key regional markets.

Market Forecast by Consumption: The consumption and consumption value forecasts included in this section are for the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market as well as for key regional markets.

Value Chain and Sales Analysis: It deeply analyzes customers, distributors, sales channels, and value chain of the global Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market.

Key Findings: This section gives a quick look at important findings of the research study.

About SDMR: We have a strong network of high powered and experienced global consultants who have about 10+ years of experience in the specific industry to deliver quality research and analysis. Having such an experienced network, our services not only cater to the client who wants the basic reference of market numbers and related high growth areas in the demand side, but also we provide detailed and granular information using which the client can definitely plan the strategies with respect to both supply and demand side.

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Viral Vectors, Non-Viral Vectors and Gene Therapy Manufacturing Market | Competitive Analysis, Industry Dynamics, Growth Factors and Opportunities |...

Recommendation and review posted by Bethany Smith

Alan Smith, Ph.D., Joins as Chief Technology Officer

Saira Ramasastry Joins Board of Directors; Arthur Tzianabos, Ph.D., Role Expanded to Chairman

BOSTON, Aug. 05, 2020 (GLOBE NEWSWIRE) -- Akouos, Inc. (Akouos) (Nasdaq: AKUS), a precision genetic medicine company dedicated to developing potential gene therapies for individuals living with disabling hearing loss worldwide, today announced the appointment of Alan Smith, Ph.D., as chief technology officer. In addition, the company announced that Saira Ramasastry has been appointed to its board of directors as audit committee chair, and board member Arthur Tzianabos, Ph.D., has been appointed chairman of the board.

Alan brings terrific experience in the development and manufacturing of complex biologics, and a proven track record of building teams and establishing infrastructure to support in-house GMP manufacturing capabilities, said Manny Simons, Ph.D., founder, president, and chief executive officer of Akouos. Alan joins Akouos at a pivotal time as we prepare to advance our lead program, AK-OTOF, to IND submission next year. We are also excited to welcome Saira, an esteemed life science leader, to our board of directors, and delighted to expand Arthurs role to chairman of our board. Together, these appointments will be instrumental as Akouos continues to grow into a fully integrated genetic medicine company developing innovative potential therapies for a variety of inner ear disorders.

Dr. Smith joins Akouos with more than 30 years of experience in research and development, manufacturing, and quality in the areas of cell and gene therapies. He has contributed to more than 25 FDA regulatory submissions for cell therapy products and devices. Prior to Akouos, Dr. Smith was executive vice president, technical operations at Bellicum Pharmaceuticals, where he led cell product manufacturing, viral vector manufacturing, process development, assay development, GMP supply chain and logistics, worldwide facilities functions, and the design, construction, and startup of multiple GMP manufacturing facilities. Previously, Dr. Smith was vice president of research and development and cellular therapeutics for LifeNet Health and its subsidiary, The Institute of Regenerative Medicine. Earlier in his career, Dr. Smith served as president and chief executive officer for Cognate BioServices Inc. and chief operating officer and senior vice president of research and development for Osiris Therapeutics, Inc. Dr. Smith is also a former adjunct professor at Eastern Virginia Medical School, California State University, Long Beach and Utah State University. He holds a B.S. in chemistry from Southern Utah University and a Ph.D. in biochemistry from Utah State University.

Ms. Ramasastry is managing partner of Life Sciences Advisory, a firm that she founded to provide strategic advice and business development solutions for life science companies. Ms. Ramasastry is also a health innovator fellow of the Aspen Institute and a member of the Aspen Global Leadership Network. Prior to founding Life Sciences Advisory, Ms. Ramasastry was an investment banker with Merrill Lynch & Company, where she helped establish the biotechnology practice and was responsible for origination of mergers and acquisitions, and strategic and capital markets transactions. Prior to joining Merrill Lynch, she served as a financial analyst in mergers and acquisitions group at Wasserstein Perella & Co., an investment banking firm. Ms. Ramasastry currently serves on the board of directors for Vir Biotechnology Inc., Glenmark Pharmaceuticals Ltd., and Sangamo Therapeutics, Inc. She holds a B.A. in economics with honors and distinction and an M.S. in management science and engineering from Stanford University, as well as an M. Phil. in management studies from the University of Cambridge, where she is a guest lecturer for the Bioscience Enterprise Programme and previously served on the Cambridge Judge Business School Advisory Council.

Initially appointed as an independent director to Akouoss board of directors in July 2018, Dr. Tzianabos has now been appointed to serve as chairman. Dr. Tzianabos is currently the chief executive officer and president of Homology Medicines, Inc., leading the efforts to develop genetic medicines for patients with rare genetic diseases. Previously, Dr. Tzianabos spent nine years at Shire Plc, where he worked on the development and launches of multiple treatments for patients with rare genetic disorders. Prior to joining Shire, Dr. Tzianabos was an Associate Professor of Medicine at Harvard Medical School and maintained laboratories at the Channing Laboratory, Brigham and Womens Hospital and the Department of Microbiology and Molecular Genetics at Harvard Medical School. He serves on the board of directors for Stoke Therapeutics, Inc., the Alliance for Regenerative Medicine, and the development board for the University of New Hampshires College of Life Sciences and Agriculture. Dr. Tzianabos holds a B.S. in biology from Boston College and a Ph.D. in Microbiology from the University of New Hampshire.

About AkouosAkouos is a precision genetic medicine company dedicated to developing gene therapies with the potential to restore, improve, and preserve high-acuity physiologic hearing for individuals living with disabling hearing loss worldwide. Leveraging its precision genetic medicine platform that incorporates a proprietary adeno-associated viral (AAV) vector library and a novel delivery approach, Akouos is focused on developing precision therapies for forms of sensorineural hearing loss. Headquartered in Boston, Akouos was founded in 2016 by leaders in the fields of neurotology, genetics, inner ear drug delivery, and AAV gene therapy.

Contact

Media:Katie Engleman, 1ABkatie@1abmedia.com

Investors:Courtney Turiano, Stern Investor RelationsCourtney.Turiano@sternir.com

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Akouos Announces Expansion of Executive Team and Board of Directors - BioSpace

Recommendation and review posted by Bethany Smith

A lone genetic mutation can cause a life-changing disorder with effects on multiple body systems. Lysosomal storage diseases, for example, of which there are dozens, arise due to single mutations that affect production of critical enzymes required to metabolize large molecules in cells. These disorders affect multiple organs including, notably, the brain, causing intellectual disability of varying degrees.Gene therapy holds promise to address these conditions, but the brains own protective mechanism the blood-brain barrier has been a formidable challenge for researchers working to develop one.

In a new study published in the journal Brain, a team led by John H. Wolfe, a researcher with Penns School of Veterinary Medicine and Perelman School of Medicine and the Childrens Hospital of Philadelphia, successfully applied a gene therapy platform to completely correct brain defects in a large animal model of a human genetic disease.

This is the first example of a large-brain mammal with a bona fide human genetic disease that has intellectual disability as part of the human syndrome where weve been able to correct the biochemistry and pathologic lesions in the whole brain, says Wolfe.

Wolfe has worked on models of human genetic diseases that impact the brain for many years. With gene therapy, a delivery vehicle typically a viral vector is used to provide the normal version of a mutated gene to correct a condition. Wolfe and other scientists working in this area have made steady progress to treat neurogenetic diseases in rodents. However, applying the same treatment to the much larger brain of higher mammals has only been able to produce partial corrections.

Theres been a lot of excitement for the last 10 years or so that specific vectors can be injected into the blood and enter the brain, says Wolfe. They do cross the blood-brain barrier. One such treatment with restricted distribution has been effective in treating a disease that primarily affects the spinal cord.

And while scientists have shown these therapies can reverse the pathology throughout the brains of mice, its been hard to judge what effect it would have in patients, as the rodent brains have a much smaller cerebral cortex than larger mammals, like humans.

In the current study, the team used an animal model with a brain more similar to humans, cats, to assess the effectiveness of a gene-correcting therapy for one type of lysosomal storage disease: a condition called alpha-mannosidosis, which naturally occurs in cats and results from a mutated copy of the alpha-mannosidase gene.

Having refined the gene delivery technique during many years of work, the researchers selected a specific vector that they showed, in mice, was capable of crossing the blood-brain barrier to reach sites throughout the brain.

They next delivered the vector, containing a reporter gene, to normal cats. Several weeks later, they were able to find evidence that the corrected gene had distributed to various parts of the brain, including the cerebral cortex, hippocampus, and mid-brain.

Finally the research team assessed the therapy in cats with alpha-mannosidosis, using either a low or high dose of the vector. They injected the therapy into the carotid artery, so that it would go directly to the brain before traveling to other parts of the body. Compared to untreated cats, treated animals had a significant delayed onset of certain neurological symptoms and a longer lifespan; those that received the higher dose of the vector delivered through the carotid artery lived the longest.

Its a big advance, says Wolfe. Nobody has been able to treat the whole brain of a large-brained animal before. Were hopeful that this will translate into clinical use in humans.

Wolfe cautions, however, the findings dont amount to a cure.

These were significant improvements, but they were only just improvements on a serious condition, Wolfe says. The cats werent cured, and we dont know what impact this has on mental ability. However, since the pathology is found throughout the brain, it is thought that complete correction will be necessary.

As alpha-mannosidosis is a childhood-onset disease with no cure, however, any improvements that lessen the severity of symptoms are welcome. The approach the researchers developed may potentially be employed to treat many other diseases that affect the whole central nervous system.

In future work, Wolfe and his collaborators hope to refine their methods to achieve the same outcomes with a lower dose, making an effective treatment safer as well as more affordable. And they will continue to work to understand the details of why their treatment works, including precisely how the vector travels through the brain, a line of investigation that could shed light on additional strategies to address these serious disorders.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Link:
Gene Therapy Beats the Blood-Brain Barrier To Cure Cat Disease - Technology Networks

Recommendation and review posted by Bethany Smith

Portland, OR, Aug. 05, 2020 (GLOBE NEWSWIRE) -- According to the report, the global Gene Therapy Marketwas pegged at$393.35 millionin 2018, and is projected to reach$6.21 billionby 2026, registering a CAGR of 34.8% from 2019 to 2026. The report offers an extensive analysis of changing market dynamics, key winning strategies, business performance, major segments, and competitive scenarios.

High investment in R&D activities, increase in prevalence of cancer, and growth in awareness regarding gene therapy have boosted the growth of the global gene therapy market. However, high costs associated with gene therapies and unwanted immune responses hamper the market growth. On the contrary, untapped potential for the emerging market is expected to create lucrative opportunities in the near future.

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Covid-19 scenario:

The viral vector segment held the largest share in 2018, contributing to more than half of the global gene therapy market, owing to easier modifications of many viruses such as Lentivirus, Adeno-Associated Virus (AAV), RetroVirus & Gamma RetroVirus to deliver gene therapy drugs. However, the non-viral vector segment is expected to register the fastest CAGR of 38.8% during the forecast period. This is attributed to the technological advancements in physicochemical approaches such as physical methods and chemical methods of non-viral vectors.

The tumor suppressor segment to portray the fastest CAGR of 52.9% during the forecast period, owing to rise in number of methodology and clinical trials of tumor suppressor for the gene therapy treatment. However, the antigen segment held the largest share in 2018, contributing to more than one-fifth of the global gene therapy market, due to the presence of a wide range of genetic mutations and dysregulated gene expression of tumor cells.

The global gene therapy market acrossNorth Americaheld the largest share in 2018, accounting for nearly half of the market, owing to high prevalence rate of cancer, presence of high disposable income, and increase in funding for R&D activities associated with gene therapy. However, the market across theAsia-Pacificregion is projected to register the fastest CAGR of 45.4% during the forecast period, owing to rise in number of people prone to various chronic diseases and approval & launch of gene therapy products.

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The key players operating in the global gene therapy market include Adaptimmune Therapeutics Plc., Anchiano Therapeutics Ltd., Achieve Life Sciences, Inc., Adverum Biotechnologies, Inc., Abeona Therapeutics Inc., Applied Genetic Technologies Corporation, Arbutus Biopharma Corporation, Audentes Therapeutics, Inc., AveXis, Inc., Bluebird Bio, Inc., Celgene Corporation, CRISPR Therapeutics AG, Editas Medicine, Inc., Editas Medicine, Inc., GlaxoSmithKline Plc., Intellia Therapeutics, Inc., Merck & Co., Inc., Novartis AG, REGENXBIO Inc., Spark Therapeutics, Inc., Sangamo Therapeutics, Inc., Uniqure N. V., Voyager Therapeutics, Inc. Other prominent players in the value chain (companies not profiled in the report) includes Amgen, Epeius Biotechnologies, Sanofi, Juno Therapeutics, and Advantagene.

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Gene Therapy Market to Reach $6.21 Billion by 2026: Allied Market Research - GlobeNewswire

Recommendation and review posted by Bethany Smith

In-depth Analysis and Data-driven Insights on the Impact of COVID-19 Included in this Global Cell and Gene Therapy Market Report. The global cell and gene therapy market by revenue is expected to grow at a CAGR of over 30.

New York, Aug. 04, 2020 (GLOBE NEWSWIRE) -- Reportlinker.com announces the release of the report "Cell & Gene Therapy Market - Global Outlook and Forecast 2020-2025" - https://www.reportlinker.com/p05827567/?utm_source=GNW 90% during the period 20192025.

The global cell and gene therapy market is one of the fastest-growing segments in the regenerative medicine market. The market is expected to grow at a faster pace during the forecast period. The demand can be attributed to the growing prevalence of several chronic diseases such as cancer, cartilage related problems, wounds, diabetic foot ulcer, genetic disorders, and other rare diseases across the globe. The prevalence of cancer and diabetes is increasing in the global population, which is influencing the growth of the market. There is a large unmet need in the treatment available, which is filled by cell and gene therapies. The market is growing due to the increased availability of funding from various public and private institutions. Besides, there is increased support from regulatory bodies for product approval. Several governments are creating awareness of cell and gene therapies in the population.

The following factors are likely to contribute to the growth of the cell and gene therapy market during the forecast period: Increase in Strategic Acquisition Activities Increased Funding for Cell & Gene Therapy Products Expanding Applications of Cell and Gene Therapies Increased in the Patient Pool

The study considers the present scenario of the cell and gene therapy market and its market dynamics for the period 2019?2025. It covers a detailed overview of several market growth enablers, restraints, and trends. The report offers both the demand and supply aspects of the market. It profiles and examines leading companies and other prominent ones operating in the market. Cell And Gene Therapy Market Segmentation The global cell and gene therapy market research report includes a detailed segmentation by product, disease, end-user, and geography. In 2019, the cell therapy segment accounted for a market share of over 53% in the global cell and gene therapy market. The segment is expected to grow at a steady rate during the forecast period due to the increase in the target population and the rise in the number of countries preferring cell therapies in their patients. Increased therapeutic benefits are attracting several countries to invest in this technology and conduct a high number of clinical trials. However, the lack of advanced infrastructure in developing countries is hindering the growth of the segment.

In 2019, the oncology segment accounted for a share of over 40% in the global cell and gene therapy market. Oncology has been one of the targets of intense research for the gene therapy procedures & approach. More than 60% of on-going gene therapy clinical trials are targeting cancer. The segment is expected to grow at a promising rate on account of the high prevalence of cancer diseases, especially in low and middle-come countries. The market is growing at a double-digit CAGR, which is expected to help the segment as many cell and gene therapy for cancer are commercially available.

The dermatology application segment in the cell and gene therapy includes wound care management among patients. Vendors are focusing on the development and commercialization of advanced wound care products for the treatment of chronic and acute wounds, thereby increasing the growth of the wound care market. The increased pervasiveness of diabetics is increasing acute and chronic wounds, including surgical wounds, pressure ulcers, diabetic foot ulcers, and other wounds.

In 2019, the oncology segment accounted for a share of over 40% in the global cell and gene therapy market. Oncology has been one of the targets of intense research for the gene therapy procedures & approach. More than 60% of on-going gene therapy clinical trials are targeting cancer. The segment is expected to grow at a promising rate on account of the high prevalence of cancer diseases, especially in low and middle-come countries. The market is growing at a double-digit CAGR, which is expected to help the segment as many cell and gene therapy for cancer are commercially available.

The dermatology application segment in the cell and gene therapy includes wound care management among patients. Vendors are focusing on the development and commercialization of advanced wound care products for the treatment of chronic and acute wounds, thereby increasing the growth of the wound care market. The increased pervasiveness of diabetics is increasing acute and chronic wounds, including surgical wounds, pressure ulcers, diabetic foot ulcers, and other wounds.

Segmentation by Product Cell Therapy Gene Therapy Segmentation by Disease Dermatology Musculoskeletal Oncology Genetic Disorders Others Segmentation by End-user Hospitality Cancer Care Centers Wound Care Centers Ambulatory Surgical Centers Others

INSIGHTS BY GEOGRAPHY In 2019, North America accounted for a share of over 60% of the global cell and gene therapy market. There are more than 530 regenerative medicine companies, including cell and gene therapy manufacturing developers. The number of products approved in North America grew significantly in 2019, with developers filed for marketing authorization for 10+ regenerative medicines, many of which we expect to be approved in 2020. Within the next 12 years, the number of approved gene therapies is expected to double. The US and Canada are the major contributors to the cell and gene therapy market in North America. Regulatory bodies are supporting several investigational products, fast track approvals, RMAT designation for the faster approval of the product into the market. The alliance for regenerative medicine and Medicare and Medicaid is working together to bring the structured reimbursement channels for cell and gene therapies.

Segmentation by Geography North America o US o Canada Europe o UK o Germany o France o Spain o Italy APAC o China o Japan o South Korea o Australia o India Latin America o Brazil o Mexico Middle East & Africa o Saudi Arabia o Turkey o South Africa o UAE

INSIGHTS BY VENDORS The global cell and gene therapy market is highly dynamic and characterized by the presence of several global, regional, and local vendors offering a wide range of therapies. Dendreon, Gilead Sciences, Novartis, Organogenesis, Osiris Therapeutics, Vericel, Amgen, and Spark Therapeutics are the leading players in the market with significant shares. Vendors such as NuVasive, APAC Biotech, Nipro, Orthocell, bluebird bio, J-TEC, and Terumo are the other prominent players in the market with a presence, especially in the cell therapy market. Most leading players are focusing on implementing strategies such as product launches and approvals, marketing and promotional activities, acquisitions, increased R&D investments, and strengthening their distribution networks to enhance their share and presence in the market.

Prominent Vendors Gilead Sciences Spark Therapeutics Novartis Organogenesis Amgen Osiris Therapeutics Dendreon Vericel

Other Prominent Vendors Anterogen Tego Sciences Japan Tissue Engineering JCR Pharmaceuticals Medipost MolMed AVITA Medical CollPlant Biosolution Stempeutics Research Kolon Tissue Gene Orchard Therapeutics Sibiono GeneTech NuVasive Corestem Pharmicell Shanghai Sunway Biotech RMS Regenerative Medical System Takeda Pharmaceutical Company CHIESI Farmaceutici CO.DON AnGes GC Pharma Human Stem Cells Institute JW CreaGene APAC Biotech Nipro Terumo Orthocell bluebird bio

Key Questions Answered 1. What is the cell and gene therapy market size and growth rate during the forecast period? 2. What are the factors impacting the growth of the cell and gene therapy market share? 3. How is the growth of the healthcare segment affecting the growth of the cell and gene therapy market? 4. Who are the leading vendors in the cell and gene therapy market, and what are their market shares? 5. Which product type/ end-user type/region is generating the largest revenue in the Asia Pacific region?Read the full report: https://www.reportlinker.com/p05827567/?utm_source=GNW

About ReportlinkerReportLinker is an award-winning market research solution. Reportlinker finds and organizes the latest industry data so you get all the market research you need - instantly, in one place.

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The global cell and gene therapy market by revenue is expected to grow at a CAGR of over 30.90% during the period 20192025 - Yahoo Finance

Recommendation and review posted by Bethany Smith

PALO ALTO, Calif. and RESEARCH TRIANGLE PARK, N.C., Aug. 4, 2020 /PRNewswire/ --Kriya Therapeutics announced today that it has secured a 51,350 square foot operational manufacturing facility in Research Triangle Park (RTP), North Carolina to support the scalable production of its pipeline of AAV-based gene therapies for highly prevalent serious diseases. The facility is designed to have its own fully integrated process development lab, quality control and analytical development capability, pilot production suite, and current good manufacturing practice (cGMP) production infrastructure. Kriya will manufacture gene therapies at the facility using its scalable suspension cell culture manufacturing process at up to 2,000-liter bioreactor scale. The facility's pilot production suite and full cGMP manufacturing infrastructure are expected to be online in the first and second half of 2021, respectively.

"Manufacturing continues to be a critical bottleneck to the advancement of gene therapies for prevalent diseases," said Britt Petty, Chief Manufacturing Officer at Kriya Therapeutics. "With the establishment of our cGMP manufacturing facility in North Carolina, we are preparing to have the capacity to support our pipeline of programs addressing large patient populations, from initial INDs through late-phase clinical studies. Moreover, we are investing in process innovation and scalable infrastructure with the goal of reducing the cost of goods of our therapies by orders of magnitude."

"As we develop our platform technologies and advance our pipeline of gene therapies, we are committed to securing the capacity to support the manufacturing of our products at scale," said Shankar Ramaswamy, M.D., Co-Founder, Chairman, and CEO of Kriya Therapeutics. "Our investment in our RTP facility helps establish this capability in a region with tremendous talent in gene therapy manufacturing, while also enabling our team to focus on innovations to bring down the cost of goods of our gene therapies."

About Kriya Therapeutics

Kriya Therapeutics is a next-generation gene therapy company focused on developing transformative treatments for highly prevalent serious diseases. With core operations in California and North Carolina, Kriya's technology-enabled platform is directed to the rational design and clinical translation of gene therapies for large patient populations. For more information, please visit http://www.kriyatx.com.

Cautionary Note on Forward-Looking Statements

This press release includes forward-looking statements pertaining to the usage and capabilities of our manufacturing facility, our costs, and the potential of our platform. Such forward-looking statements are subject to risks and uncertainties that could cause actual results to differ materially from those expressed or implied in such statements. The forward-looking statements contained in this press release reflect Kriya's current views with respect to future events, and Kriya does not undertake and specifically disclaims any obligation to update any forward-looking statements.

Contact Daniel Chen Chief Financial Officer [emailprotected]

SOURCE Kriya Therapeutics

https://www.kriyatx.com/

Link:
Kriya Therapeutics announces the establishment of its internal manufacturing facility for process development and scalable cGMP production of gene...

Recommendation and review posted by Bethany Smith

NEW YORK--(BUSINESS WIRE)--IVERIC bio, Inc. (Nasdaq: ISEE) today announced financial and operating results for the fiscal quarter ended June 30, 2020 and provided a general business update.

Following the positive results from our GATHER1 Phase 3 clinical trial of Zimura for the treatment of geographic atrophy secondary to age-related macular degeneration, our main priority is to aggressively drive patient recruitment and retention in GATHER2, our second Phase 3 clinical trial for the treatment of GA secondary to AMD, stated Glenn P. Sblendorio, Chief Executive Officer and President of IVERIC bio. We believe GATHER1 is currently the only Phase 3 clinical trial showing early suppression of GA growth which continued for 18 months with continuous treatment. The enthusiasm, resiliency and dedication of patients, physicians and their staffs fueled by their confidence in the GATHER1 Phase 3 results are exceeding our expectations.

Mr. Sblendorio added, During the second quarter, we strengthened our balance sheet with a public offering and a concurrent private placement. We believe this enables us to further execute on our strategy to develop and deliver retinal treatments through our Zimura, gene therapy and HtrA1 inhibitor programs, with the potential to create long-term shareholder value.

Age-Related Macular Degeneration Programs

Zimura (avacincaptad pegol): Complement C5 Inhibitor

IC-500: HtrA1 (high temperature requirement A serine peptidase 1 protein) Inhibitor

Gene Therapy Programs in Orphan Inherited Retinal Diseases (IRDs)

Corporate UpdateIn April 2020, the Company appointed Pravin U. Dugel, MD as Executive Vice President and Chief Strategy and Business Officer. In July 2020, Mark S. Blumenkranz, MD, MMS, joined its board of directors.

Second Quarter 2020 Operational Update and Cash GuidanceAs of June 30, 2020, the Company had $245.7 million in cash and cash equivalents. In June 2020, the Company raised approximately $150 million in net proceeds in an underwritten public offering of common stock, and pre-funded warrants in lieu of common stock, and a concurrent private placement of common stock. The Company now estimates that its year-end 2020 cash and cash equivalents will range between $215 million and $220 million. The Company also estimates that its cash and cash equivalents will be sufficient to fund its currently planned capital expenditure requirements and operating expenses, excluding any potential approval or sales milestones payable to Archemix Corp. or any commercialization expenses for Zimura, through at least mid-2024. These estimates are based on the Companys current business plan, which includes the continuation of the Companys clinical development programs for Zimura, the progression of the Companys IC-100 and IC-200 programs into the clinic, and the advancement of the Companys IC-500 development program. These estimates assume that the Company will enroll approximately 400 patients in the GATHER2 trial. These estimates do not reflect any additional expenditures resulting from the potential in-licensing or acquisition of additional product candidates or technologies, commencement of any new sponsored research programs, or any associated develop that the Company may pursue.

2020 Q2 Financial Highlights

Conference Call/Web Cast InformationIVERIC bio will host a conference call/webcast to discuss the Companys financial and operating results and provide a business update. The call is scheduled for August 5, 2020 at 8:00 a.m. Eastern Time. To participate in this conference call, dial 888-220-8451 (USA) or 323-794-2588 (International), passcode 2738321. A live, listen-only audio webcast of the conference call can be accessed on the Investors section of the IVERIC bio website at http://www.ivericbio.com. A replay will be available approximately two hours following the live call for two weeks. The replay number is 888-203-1112 (USA), passcode 2738321.

About IVERIC bioIVERIC bio is a science-driven biopharmaceutical company focused on the discovery and development of novel treatment options for retinal diseases with significant unmet medical needs. The Company is currently developing both therapeutic product candidates for age-related retinal diseases and gene therapy product candidates for orphan inherited retinal diseases. Vision is Our Mission. For more information on the Company, please visit http://www.ivericbio.com.

Forward-looking StatementsAny statements in this press release about the Companys future expectations, plans and prospects constitute forward-looking statements for purposes of the safe harbor provisions under the Private Securities Litigation Reform Act of 1995. Forward-looking statements include any statements about the Companys strategy, future operations and future expectations and plans and prospects for the Company, and any other statements containing the words anticipate, believe, estimate, expect, intend, goal, may, might, plan, predict, project, seek, target, potential, will, would, could, should, continue, and similar expressions. In this press release, the Companys forward looking statements include statements about the impact of the COVID-19 pandemic on the Companys research and development programs, operations and financial position, its expectations regarding patient enrollment and patient retention in its second Phase 3 trial (GATHER2) of Zimura in geographic atrophy secondary to AMD and to use the results of its completed clinical trial of Zimura for the treatment of geographic atrophy secondary to AMD (GATHER1) as a Phase 3 trial, expectations regarding patient enrollment and patient retention in its Phase 2b screening trial of Zimura for autosomal recessive Stargardt disease, its development and regulatory strategy for Zimura and its other product candidates, the implementation of its business plan, the projected use of cash and cash balances, the timing, progress and results of clinical trials and other research and development activities and regulatory submissions, the potential utility of its product candidates, and the potential for its business development strategy. Such forward-looking statements involve substantial risks and uncertainties that could cause the Companys development programs, future results, performance or achievements to differ significantly from those expressed or implied by the forward-looking statements. Such risks and uncertainties include, among others, those related to the progression and duration of the COVID-19 pandemic and responsive measures thereto and related effects on the Companys research and development programs, operations and financial position, the initiation and the progress of research and development programs and clinical trials, availability of data from these programs, reliance on contract development and manufacturing organizations, university collaborators and other third parties, establishment of manufacturing capabilities, expectations for regulatory matters, need for additional financing and negotiation and consummation of business development transactions and other factors discussed in the Risk Factors section contained in the quarterly and annual reports that the Company files with the Securities and Exchange Commission. Any forward-looking statements represent the Companys views only as of the date of this press release. The Company anticipates that subsequent events and developments will cause its views to change. While the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so except as required by law.

2020

2019

2020

2019

$

12,720

$

10,009

$

26,470

$

17,694

6,289

5,198

11,287

10,679

19,009

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46

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1,287

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151

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151

(18,975

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(26,935

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IVERIC bio Reports Second Quarter 2020 Operational Highlights and Financial Results - Business Wire

Recommendation and review posted by Bethany Smith

The report gives a complete investigation of the Cancer Gene Therapy Market and key improvements. The exploration record comprises of past and figure showcase data, prerequisite, territories of use, value strategies, and friends portions of the main organizations by topographical district. The Cancer Gene Therapy report separates the market size, by volume and worth, depending upon the kind of utilization and area.

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Top Companies Name: Urigen Pharmaceuticals Inc. (U.S), GenVec.Inc (U.S), Oxford BioMedica (U.K), Vical (U.S), ANI Pharmaceuticals, Inc. (U.S), and Genzyme Corporation (U.S). Novartis AG and Others.

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Cancer Gene Therapy Market Latest Treatment Methodology 2020 to 2025 - Owned

Recommendation and review posted by Bethany Smith

DetailsCategory: DNA RNA and CellsPublished on Tuesday, 04 August 2020 16:01Hits: 455

ROCKVILLE, MD, USA I August 04, 2020 I REGENXBIO Inc. (Nasdaq: RGNX), a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy based on its proprietary NAVTechnology Platform, today reported positive one year data from patients in Cohorts 4 and 5 of the Phase I/IIa trial of RGX-314 for the treatment of wet age-related macular degeneration (wet AMD). The Company plans to initiate a pivotal program for subretinal delivery of RGX-314 in patients with wet AMD by the end of 2020. In addition, REGENXBIO today announced that a Phase II trial of RGX-314 for the treatment of wet AMD delivered to the suprachoroidal space (AAVIATE) is active and expected to enroll patients in the third quarter of 2020.

"Today's results provide further evidence of the clinical profile of RGX-314 as a promising one-time gene therapy treatment paradigm for patients with wet AMD," said Steve Pakola, M.D., Chief Medical Officer of REGENXBIO. "The data demonstrated stable to improved visual acuity and retinal thickness, as well as a meaningful reduction in anti-VEGF injection burden, in these higher dose levels at one year. Results from the Phase I/IIa trial will inform the design of the pivotal program of RGX-314 in patients with wet AMD, which we look forward to initiating by the end of this year."

Dr. Pakola continued: "I am also pleased to announce that our AAVIATE trial, a Phase II trial of RGX-314 for the treatment of wet AMD utilizing the SCS Microinjector, is active and we expect to dose the first patient this quarter. The targeted, in-office suprachoroidal delivery approach may provide additional options for patients in all settings of patient care. We anticipate providing an interim data update from the first cohort in late 2020."

"Based on the overall results to date from the Phase I/IIa trial, I believe that RGX-314 has the potential to profoundly impact all aspects of clinical management for patients with wet AMD," said Robert Avery, M.D., Founder of California Retina Consultants and Research Foundation and investigator surgeon in the Phase I/IIa RGX-314 trial. "Wet AMD affects a large number of adults, and often results in loss of vision over time due to non-compliance with the current standard of care of frequent anti-VEGF injections. I am encouraged that RGX-314 has the potential to become a one-time gene therapy treatment option for a broad range of patients."

Study Design and Safety Update from Phase I/IIa Trial of RGX-314 for the Treatment of Wet AMD using Subretinal Delivery

In the Phase I/IIa trial of RGX-314, 42 patients with long-standing severe wet AMD requiring frequent anti-vascular endothelial growth factor (anti-VEGF) injections were treated across five dose cohorts, with doses ranging from 3x109 GC/eye to 2.5x1011 GC/eye. Patients were enrolled into all dose cohorts independent of their neutralizing antibody titers to AAV and did not receive prophylactic or supplemental immune suppressive corticosteroid therapy for RGX-314.

Patients in the study are being assessed each month for two years and will receive safety follow-up for five years after RGX-314 administration. Efficacy assessments for the study include number of anti-VEGF intravitreal injections, change in vision as measured by Best Corrected Visual Acuity (BCVA), change in central retinal thickness (CRT) as measured by spectral domain optical coherence tomography (SD-OCT), and RGX-314 protein expression levels as measured from aqueous samples by electrochemiluminescence immunoassay (ECL).

As of July 13, 2020, RGX-314 was generally well-tolerated across all cohorts. Eighteen serious adverse events (SAEs) were reported in 11 patients, including 17 that were not related to RGX-314. One possibly drug-related SAE of significant decrease in vision was reported in Cohort 5 at Month 11 in a patient who had retinal pigmentary changes that involved the macula. The most common nonserious adverse events in the eye were generally assessed as mild (77%). These included post-operative conjunctival hemorrhage (69% of patients), post-operative inflammation (36% of patients), eye irritation (17% of patients), eye pain (17% of patients), and post-operative visual acuity reduction (17% of patients). In 67% of patients across all cohorts, and in 83% of patients in Cohorts 3 through 5, retinal pigmentary changes were observed on imaging, the majority of which were in the peripheral inferior retina. Retinal hemorrhage was observed in 24% of patients and is an anticipated event in patients with severe wet AMD. There have been no reports of clinically determined immune responses, drug-related ocular inflammation, or post-surgical inflammation beyond what is expected following routine vitrectomy.

Summary of Data from Cohorts 4 and 5 of Phase I/IIa Trial of RGX-314 for the Treatment of Wet AMD using Subretinal Delivery

Today's update includes data from Cohorts 4 and 5 as of July 13, 2020. Each cohort enrolled 12 patients each at doses of 1.6x1011 GC/eye and 2.5x1011 GC/eye, respectively.

Patients in Cohort 4 and Cohort 5 at one year after administration of RGX-314 demonstrated stable visual acuity with a mean BCVA change of +4 letters and -2 letters from baseline, respectively, as well as decreased retinal thickness, with a mean change in CRT of -61 m and -79 m, respectively.

There was a clinically significant and meaningful reduction in anti-VEGF treatment burden in both Cohorts 4 and 5 compared to the 12 months prior to RGX-314 administration. Patients in Cohort 4 received a mean of 4.1 injections over one year following administration of RGX-314, a 61% reduction in treatment burden. Patients in Cohort 5 received a mean of 1.4 injections over one year following administration of RGX-314, a reduction in treatment burden of 85%.

In Cohort 4, three out of twelve (25%) patients received no anti-VEGF injections over one year, and these patients demonstrated a mean BCVA improvement of +6 letters and a mean reduction in CRT of -62 m at one year. In Cohort 5, eight out of the eleven (73%) patients observed through one year have received no anti-VEGF injections after administration of RGX-314 and these patients demonstrated a stable mean BCVA change of 0 letters and a mean reduction in CRT of -95 m at one year.

Consistent with previous results, intraocular RGX-314 protein expression levels were observed in a dose-dependent manner across each cohort at one year after administration of RGX-314. The mean protein expression levels in Cohort 4 and Cohort 5 were 420.9 ng/ml and 457.5 ng/ml, respectively.

Study Design for Phase II Trial for RGX-314 for Treatment of Wet AMD using Suprachoroidal Delivery (AAVIATE)

REGENXBIO also announced that a Phase II trial, AAVIATE, to evaluate the suprachoroidal delivery of RGX-314 in patients with wet AMD, will begin dosing patients in the third quarter of 2020. AAVIATE is a multi-center, open-label, randomized, active-controlled, dose-escalation study that will evaluate the efficacy, safety and tolerability of suprachoroidal delivery of RGX-314 using the SCS Microinjector, a targeted, in-office route of administration.

AAVIATE will enroll 40 patients with severe wet AMD who are responsive to anti-VEGF treatment. Patients will be randomized to one-time RGX-314 SCS delivery versus monthly 0.5 mg ranibizumab intraocular injection at a 3:1 ratio and two dose levels of RGX-314 will be evaluated: 2.5x1011 GC/eye and 5x1011 GC/eye.Patients will not receive prophylactic immune suppressive corticosteroid therapy before or after administration of RGX-314.

The primary endpoint of the study is mean change in vision, as measured by BCVA, at 40 weeks from baseline compared to monthly ranibizumab. Other endpoints include mean change in CRT and number of anti-VEGF intravitreal injections.

The Company expects to report interim data from the first cohort of this trial by the end of 2020.

About RGX-314

RGX-314 is being developed as a potential one-time treatment for wet AMD, diabetic retinopathy, and other additional chronic retinal conditions treated with anti-VEGF. RGX-314 consists of the NAV AAV8 vector encoding an antibody fragment which is designed to inhibit VEGF, modifying the pathway for formation of new leaky blood vessels which lead to retinal fluid accumulation and vision loss.

About the Phase I/IIa Clinical Trial of RGX-314

RGX314 is being evaluated in a Phase I/IIa, multi-center, open-label, multiple-cohort, doseescalation study in adult patients with wet AMD in the United States. The study includes patients previously treated for wet AMD who are responsive to anti-VEGF therapy. The study is designed to evaluate five escalating doses of RGX-314, with six patients in the first three dose cohorts and 12 patients in the fourth and fifth dose cohorts. Patients were enrolled into all dose cohorts independent of their neutralizing antibody titers to AAV and did not receive prophylactic immune suppressive oral corticosteroid therapy before or after administration of RGX-314. The primary endpoint of the study is safety at 6 months following administration of RGX-314. Secondary endpoints include visual acuity, retinal thickness on SDOCT, ocular RGX-314 protein expression, and the need for additional anti-VEGF therapy. Following completion of the primary study period, patients enter a follow-up period and will continue to be assessed until week 106 for long-term safety and durability of effect.

About Wet AMD

Wet AMD is characterized by loss of vision due to new, leaky blood vessel formation in the retina. Wet AMD is a significant cause of vision loss in the United States, Europe and Japan, with up to 2 million people living with wet AMD in these geographies alone. Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to prevent progression of vision loss in the majority of patients. These therapies, however, require life-long intraocular injections, typically repeated every four to 12 weeks in frequency, to maintain efficacy. Due to the burden of treatment, patients often experience a decline in vision with reduced frequency of treatment over time.

AboutREGENXBIO Inc.

REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. REGENXBIO's NAV Technology Platform, a proprietary adeno-associated virus (AAV) gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10. REGENXBIO and its third-party NAV Technology Platform Licensees are applying the NAV Technology Platform in the development of a broad pipeline of candidates in multiple therapeutic areas.

SOURCE: REGENXBIO

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REGENXBIO Announces Additional Positive Interim Phase I/IIa Trial Update and Program Updates for RGX-314 for the Treatment of Wet AMD | DNA RNA and...

Recommendation and review posted by Bethany Smith