Sunnybrook Hospital is shown in Toronto on Sunday Jan. 26, 2020. (The Canadian Press/Doug Ives)

A $16.7 million grant from the W. Garfield Weston Foundation will fund research for a new innovative way to treat brain diseases and disorders such as cancer and Alzheimers according to a press release from the Sunnybrook Health Sciences Centre from earlier this week.

Through the Weston Brain Institute, the W. Garfield Weston Foundation has established the Weston Family Focused Ultrasound Initiative at Sunnybrook, which is a health sciences centre researching and inventing the future of health care.

According to the press release the funding will go towards an initiative to create an one size fits all ultrasound device that promises to deliver a personalised way to treat brain diseases.

We are delighted to make this contribution to improve the treatment of brain diseases, Galen G. Weston, the president of The W. Garfield Weston Foundation said in a press release. This initiative is a unique opportunity to accelerate the development of this breakthrough technology while encouraging leadership and innovation in the Canadian medical technology sector.

The prospect of readying this device to benefit so many people in Canada and around the world is very exciting, he added.

The device will use focused ultrasound to open the blood brain barrier, which is the packed network of vessels that protects the brain from toxins, but also prevents the brain from getting help from treatments, such as chemotherapy, stem cells, or gene therapy.

Dr. Kullervo Hynynen, a physicist, the vice president of research innovation at Sunnybrook, and leads the team working on the prototype device, said that the vessels in the brain are special because they protect the brain from foreign agents.

They do not allow most of the medication to enter into brain cells, he said. This device will allow us to modulate that barrier and blood brain barrier and allow medications to get into that brain in the specified locations.

A prototype of a new device which will be custom-built for each patient and will deliver focused ultrasound without the need for real-time MRI is shown in a handout photo from Sunnybrook Hospital. Sunnybrook Hospital says a landmark $16.7-million grant could revolutionize the treatment of brain disorders including Alzheimers, brain cancer and ALS. (The Canadian Press/HO-Sunnybrook Hospital/Jason Mortlock)

Once the device is developed, Sunnybrook will launch three clinical trials to test the device and showcase the technology.

This technology holds tremendous promise for patients with difficult-to-treat brain disorders like Alzheimers disease, brain cancer and ALS, where the blood-brain barrier is a major obstacle, said Dr. Nir Lipsman, a neurosurgeon thats leading Sunnybrooks clinical team.

These are some of the most complex disorders that have no effective treatments, so were excited to move closer to testing the device in clinical trials. The impact of this technology on patient care will be felt across Canada and around the world.

The whole initiative is going to cost about $33 million, therefore Sunnybrook is looking towards the community to secure the rest of the funding it needs to complete its research.

See the original post here:
Philanthropic grant funds research for innovative way to treat brain disorders - Radio Canada International (en)

Recommendation and review posted by Bethany Smith

In the months since the novel coronavirus rose from a regional crisis to a global threat, drug makers large and small have scrambled to advance their best ideas for thwarting a pandemic.

Some are repurposing old antivirals. Some are mobilizing tried-and-true technologies, and others are pressing forward with futuristic approaches to human medicine.

Heres a guide to some of the most talked-about efforts to treat or prevent coronavirus infection, with details on the science, history, and timeline for each endeavor.

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Approach: TreatmentStage: Phase 3

Gileads remdesivir, an intravenous treatment, has already been used to treat one infected patient in the U.S. and will soon be deployed in a pair of large, late-stage studies in Asia. Later this month, Gilead will recruit about 1,000 patients diagnosed with the coronavirus to determine whether multiple doses of remdesivir can reverse the infection. The primary goals are reducing fever and helping patients get out of the hospital within two weeks. The drug, which previously failed in a study on Ebola virus, is also being studied in smaller trials in China and the U.S.

Approach: VaccineStage: Phase 1

Moderna set a drug industry record with mRNA-1273, a vaccine candidate identified just 42 days after the novel coronavirus was sequenced. The company is working with the National Institutes of Health on a healthy-volunteer study expected to begin next month. If mRNA-1273 proves itself to be safe, the two organizations will enroll hundreds more patients to determine whether the vaccine protects against infection. Modernas product is a synthetic strand of messenger RNA, or mRNA, designed to convince bodily cells to produce antibodies against the virus. The company, founded in 2010, is yet to win Food and Drug Administration approval for any of its mRNA medicines.

Approach: VaccineStage: Preclinical

Like Moderna, CureVac uses man-made mRNA to spur the production of proteins. And, like Moderna, it got a grant from the nonprofit Coalition for Epidemic Preparedness Innovations to apply its technology to coronavirus. CureVac has said it expects to have a candidate ready for human testing within a few months. The company is also working with CEPI on a mobile mRNA manufacturing technology, one that would theoretically allow health care workers to rapidly produce vaccines to respond at the site of an outbreak.

Approach: VaccineStage: Preclinical

GlaxoSmithKline, one of the worlds largest vaccine manufacturers, is lending its technology to a Chinese biotech firm at work on a coronavirus vaccine. Under an agreement signed last month, GSK is providing its proprietary adjuvants compounds that enhance the effectiveness of vaccines to Clover Biopharmaceuticals, a privately held company based in Chengdu. Clovers approach involves injecting proteins that spur an immune response, thereby priming the body to resist infection. The company has not said when it expects to advance into human testing.

Approach: VaccineStage: Preclinical

Inovio has spent the last four decades working to turn DNA into medicine, and the company believes its technology could quickly generate a vaccine for the novel coronavirus. Working with CEPI grant money, Inovio has come up with a DNA vaccine it believes can generate protective antibodies and keep patients from infection. The company has partnered with a Chinese manufacturer, Beijing Advaccine Biotechnology, and is working through preclinical development with a candidate called INO-4800. The company expects to progress into clinical trials later this year.

Approach: Vaccine and treatmentStage: Preclinical

Johnson & Johnson, which has in the past responded to outbreaks of the Ebola and Zika viruses, is taking a multipronged approach to the coronavirus. The company is in the early days of developing a vaccine that would introduce patients to a deactivated version of the virus, triggering an immune response without causing infection. At the same time, J&J is working with the federal Biomedical Advanced Research and Development Authority on potential treatments for patients who are already infected, a process that includes investigating whether any of its older medicines might work against the coronavirus.

Approach: TreatmentStage: Preclinical

Regeneron has grown into a $50 billion business based on its ability to craft human antibodies out of genetically engineered mice. Now its tapping that technology in hopes of treating coronavirus. The company is immunizing its antibody-generating mice with a harmless analog of the novel coronavirus, generating potential treatments for the infection. The most potent antibody results will go into animal testing, and if everything goes according to plan, Regeneron will be ready for human testing by late summer. The last time Regeneron embarked on this process, during the Ebola outbreak of 2015, it came up with an antibody cocktail that roughly doubled survival rates for treated patients.

Approach: VaccineStage: Preclinical

Sanofi, which has successfully developed vaccines for yellow fever and diphtheria, is working with BARDA on an answer to the coronavirus. Sanofis approach involves taking some of the coronaviruss DNA and mixing it with genetic material from a harmless virus, creating a chimera that can prime the immune system without making patients sick. Sanofi expects to have a vaccine candidate to test in the lab within six months and could be ready to test a vaccine in people within a year to 18 months. Approval would likely be at least three years away, the company said. Sanofi previously put its technology to work against SARS, a close relative of the novel virus.

Approach: TreatmentStage: Preclinical

Vir Biotechnology, a company focused on infectious disease, has isolated antibodies from people who survived SARS, a viral relative of the novel coronavirus, and is working to determine whether they might treat the infection. Teaming up with Chinese pharma contractor WuXi Biologics, the San Francisco-based Vir is in the early stages of development and hasnt specified when it expects to have products ready for human testing. Virs CEO, Biogen veteran George Scangos, is also coordinating the trade group BIOs response to the coronavirus outbreak.

View original post here:
A detailed guide to the coronavirus drugs and vaccines in development - STAT

Recommendation and review posted by Bethany Smith

Voyager Therapeutics (NASDAQ:VYGR) had its price target trimmed by Wedbush from $34.00 to $27.00 in a research note published on Wednesday morning, The Fly reports. The brokerage currently has an outperform rating on the stock. Wedbush also issued estimates for Voyager Therapeutics Q2 2020 earnings at ($0.83) EPS, FY2020 earnings at ($3.18) EPS, Q1 2021 earnings at ($0.81) EPS, Q2 2021 earnings at ($0.79) EPS, Q3 2021 earnings at ($0.71) EPS, Q4 2021 earnings at ($0.69) EPS, FY2021 earnings at ($2.99) EPS, FY2022 earnings at ($2.76) EPS, FY2023 earnings at ($2.24) EPS and FY2024 earnings at $0.29 EPS.

Several other brokerages have also issued reports on VYGR. ValuEngine raised shares of Voyager Therapeutics from a sell rating to a hold rating in a research note on Tuesday, February 25th. Zacks Investment Research lowered shares of Voyager Therapeutics from a hold rating to a sell rating in a research note on Saturday, January 25th. Oppenheimer began coverage on shares of Voyager Therapeutics in a research note on Wednesday, February 5th. They set an outperform rating and a $26.00 target price on the stock. BidaskClub raised shares of Voyager Therapeutics from a strong sell rating to a sell rating in a research note on Wednesday, February 5th. Finally, Evercore ISI reissued a hold rating and set a $18.00 target price on shares of Voyager Therapeutics in a research note on Sunday, November 24th. Two equities research analysts have rated the stock with a sell rating, four have issued a hold rating and five have given a buy rating to the company. Voyager Therapeutics has a consensus rating of Hold and a consensus price target of $22.38.

NASDAQ:VYGR opened at $10.97 on Wednesday. The firms fifty day moving average is $12.34 and its 200-day moving average is $14.70. Voyager Therapeutics has a 52 week low of $10.13 and a 52 week high of $28.79.

In other Voyager Therapeutics news, COO Matthew P. Ottmer sold 3,724 shares of the companys stock in a transaction on Tuesday, January 21st. The shares were sold at an average price of $13.36, for a total transaction of $49,752.64. Following the transaction, the chief operating officer now owns 26,276 shares in the company, valued at $351,047.36. The transaction was disclosed in a filing with the SEC, which is accessible through this link. Also, CEO Andre Turenne sold 10,705 shares of the companys stock in a transaction on Tuesday, January 21st. The stock was sold at an average price of $13.36, for a total transaction of $143,018.80. Following the transaction, the chief executive officer now owns 85,545 shares in the company, valued at approximately $1,142,881.20. The disclosure for this sale can be found here. Over the last three months, insiders have sold 17,557 shares of company stock worth $234,562. 33.60% of the stock is owned by insiders.

Institutional investors and hedge funds have recently added to or reduced their stakes in the business. Steward Partners Investment Advisory LLC raised its holdings in Voyager Therapeutics by 335.0% during the fourth quarter. Steward Partners Investment Advisory LLC now owns 4,350 shares of the companys stock worth $60,000 after buying an additional 3,350 shares during the last quarter. Victory Capital Management Inc. raised its holdings in Voyager Therapeutics by 46.0% during the fourth quarter. Victory Capital Management Inc. now owns 6,199 shares of the companys stock worth $86,000 after buying an additional 1,954 shares during the last quarter. Russell Investments Group Ltd. acquired a new position in Voyager Therapeutics during the third quarter worth $139,000. AJO LP acquired a new position in Voyager Therapeutics during the fourth quarter worth $118,000. Finally, Jackson Wealth Management LLC acquired a new position in Voyager Therapeutics during the fourth quarter worth $120,000. Hedge funds and other institutional investors own 85.69% of the companys stock.

About Voyager Therapeutics

Voyager Therapeutics, Inc, a clinical-stage gene therapy company, focuses on the development of treatments for patients suffering from severe neurological diseases. The company's lead clinical candidate is the VY-AADC, which is in open-label Phase 1b clinical trial for the treatment of Parkinson's disease.

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Wedbush Cuts Voyager Therapeutics (NASDAQ:VYGR) Price Target to $27.00 - Redmond Register

Recommendation and review posted by Bethany Smith

Ben Osborn, UK Managing Director of Pfizer, talks about his role and whats on the horizon for Pfizer and the life sciences sector.

An introduction on who you are/your role and organisation

Throughout my 20 years at Pfizer, and as a parent to a son with a chronic health condition (a rare form of epilepsy), Ive experienced how remarkable the NHS can be in more ways than most firstly, as a father of a child with ongoing and complex medical needs, and secondly as a leader at Pfizer. This gives me a unique perspective on the NHS and wider healthcare and pharmaceutical industry. I have hands-on understanding and experience of the success of the NHS and where there are challenges.

In my role as Country Manager and Managing Director, I lead Pfizer in the UK to deliver against our purpose: breakthroughs that change patients lives. We are at an exciting point in time as an organisation and as a sector, and I am passionate about what we can all do to transform patients lives and support a thriving life sciences sector. Pfizers innovation spans the rarest to the most common of diseases, and our footprint across the UK is significant with 2,500 colleagues.

What does the landscape look like for 2020 and beyond in the life sciences/health tech sector?

As we head into a new decade, we face the greatest opportunity yet to better protect and invest in our nations health. We are living through an age of unprecedented innovation as we stand at the cusp of a new era of breakthroughs which have the potential to change patients lives.

Advances in science, data and technology, in particular digital, are driving change in the health system faster than ever before, and with the new Government refocusing its efforts on our health service, we are at a pivotal moment where the latest scientific research, renewed investment and collective ambition, can come together to create the impetus for change that we need to drive better outcomes and experience for patients.

Why is collaboration so important?

Simply put, the healthcare challenges of today are simply too complex for any one organisation to solve alone, given the diversity of expertise, resources, and skills required.

The approach to innovation has changed over recent years and requires everyone to take a much more collaborative approach and form greater, deeper and stronger collaborations.

We must work together as a sector (NHS, academia, industry, and patients) and use this unparalleled opportunity to reshape UK life sciences for the better, and to support the NHS to deliver world-leading healthcare that makes a real difference to patients. No single organisation has the answer. It is only through collective action and partnership that we can deliver our shared ambition.

Whats on the horizon for Pfizer?

As a global biopharmaceutical company we are going through an exciting period of change. We have shifted to become laser-focused on a single purpose: breakthroughs that change patients lives; and at the core of our culture, of everything we do, is how we can deliver against this to make a positive contribution to patients and the society in which we live and work.

Our pipeline has the potential to transform patient outcomes and NHS service delivery across key areas, including cardiomyopathy, vaccination, osteoarthritis pain and oncology, and we also have one of the industrys deepest gene therapy pipelines. It is through our partnerships with the NHS, academia and others, in Wales and across the UK, that we will bring these therapies to patients.

We recognise the challenges faced across healthcare systems, and we want to partner to shift the historic volume-based model to one centred on outcomes and value.

Tell us what TH2020 means to you and what you are hoping to achieve and talk about.

I am excited to be talking at TH2020 and to be a part of the stimulating debate around the progressive approach to health and care that is taking place in Wales. We recognise that Wales is a leader amongst the UK nations in the way it has embraced the innovation agenda, and is blazing a trail for approaches to value-based healthcare. I want to share our vision for life sciences, and how we can work with others to transform health and care in Wales and beyond.

Continue reading here:
Exclusive Interview with Ben Osborn, UK Managing Director of Pfizer - Business News Wales

Recommendation and review posted by Bethany Smith

Is your idea of getting hot and steamy taking a shower afterspin class? Join the club. Many women discover their libido is lacking,especially as they get older.

Cleveland Clinic is a non-profit academic medical center. Advertising on our site helps support our mission. We do not endorse non-Cleveland Clinic products or services.Policy

Thats not necessarily a problem, as long as yourecomfortable with the (in)frequency of your romantic dalliances. But it can befrustrating if you miss the intimacy that goes along with sex. And if you andyour partner have mismatched libidos, that can be a big source of relationshipstrife.

Luckily, treatments are available to rev up a sluggish sex drive, says womens health specialist Holly Thacker, MD.

There are all sorts of reasons your sex drive might have shifted into neutral. Pregnancy, breastfeeding and menopause can do a number on your hormones. Stress, illness, medications and relationship challenges can also interfere with sexual desire.

If you notice a dramatic dip in your arousal level, firstrule out any medical causes. Yes, it might feel weird talking to your doctorabout getting frisky, but medical professionals have heard it all. Your Ob/Gynor primary care doctor or womens health specialist can pinpoint problems suchas medication side effects or hormonal changes (like perimenopause) that mightbe interfering with intimacy.

Yet many women experience reduced sexual desire for no obvious reason a condition sometimes called hypoactive sexual desire disorder (HSDD). And in the last few years there has been more research and medical options for this condition. We now have some excellent options, Dr. Thacker says.

Several treatments are available to turn up a womans arousal:

This prescription pill has been available to treat HSDD since 2015. Flibanserin is taken nightly and can ramp up sex drive, says Dr. Thacker. It may cause drowsiness and shouldnt be taken within 2 hours of drinking alcohol.

The downside is it takes about 2 months for the medicationto start working. But for many women (and their satisfied partners), thetreatment is worth the wait.

This on-demand prescription medication was approved totreat HSDD in 2019. Women inject it under the skin at least 45 minutes beforethey anticipate getting frisky.

Dr. Thacker notes that as many as 40% of women experiencenausea after taking the drug. So she suggests this workaround: Take it rightbefore bed and cancel your morning meetings. Since the medication lasts 16hours, youre likely to sleep through any discomfort and can enjoy the amorouseffects when the sun comes up.

This hormone suppository can ease vaginal dryness and discomfort in postmenopausal women. Some women with low libido find it increases genital sensitivity (in a good way).

Testosterone can treat low libido in women but its not approved by the Food and Drug Administration, so this off-label use is controversial. It can cause side effects, including acne, hair loss, facial hair growth and mood changes.

Medications arent always the best way to deal with a limp libido. Sometimes, low sex drive is related to psychological issues, such as poor body image, past negative sexual experiences, trust issues or relationship problems. In those cases, it can help to work through your thoughts and feelings with a mental health professional.

And some women just need a crash course in sex education,Dr. Thacker says. Learning the ins and outs of your sexual anatomy includingthe importance of clitoral and G-spot stimulation can also improve desire,she adds. After all, if it doesnt feel good, you wont crave it.

And remember that you can have a healthy sex drive withoutbeing a seductress. Most women just arent thinking about sex that often. Theyhave a more responsive reaction to sex, Dr. Thacker says.

You dont have to be the initiator to enjoy a roll in thehay. You just have to be open to it, she adds. Its like exercise: You may notfeel like doing it, but once you start, youre usually glad you did.

Read this article:
What Help Is Available for Low Sex Drive in Women? - Health Essentials from Cleveland Clinic

Recommendation and review posted by Bethany Smith

In a year when the General Assembly passed sweeping LGBTQ-friendly legislation, its a relatively low-profile health bill that has opponents questioning whether the state is going too far in its protections for transgender Virginians.

The Senate Commerce and Labor committee voted 12-2 on Monday to report a bill from Del. Danica Roem, D-Manassas, that would ban health insurance companies from denying or limiting coverage based on a patients gender identity or transgender status. The legislation, which passed the House 54-41, is expected to clear the Senate in a similarly party-line vote.

The bill codifies federal protections first established under the Affordable Care Act. In 2016, the Department of Health and Human Services issued final regulations clarifying that the law would extend nondiscrimination protections to patients on the basis of race, color, national origin, sex, age, or disability. While the federal government has never clarified that sex discrimination includes disparate treatment based on sexual orientation or transgender status (the subject of an ongoing Supreme Court case), the regulations make it clear that the federal Office for Civil Rights would consider gender identity when evaluating discrimination complaints from patients.

Since then, health insurance carriers have covered treatment thats consistent with a patients gender identity, said Doug Gray, executive director for the Virginia Association of Health Plans. That can include hormone therapy for a patient experiencing gender dysphoria the diagnostic term for someone whose gender identity doesnt align with their sex assigned at birth.

Patients dictate the extent of their treatment, but current medical standards include hormones or gender reassignment surgery. Numerous research papers, including a 2018 study on transgender veterans, have found that the treatments can significantly improve mental health outcomes and reduce the risk of suicide.

Roems bill would require carriers to cover those treatments and other medically necessary transition-related care, including mental health services. It would also ban plans from denying coverage based on a patients transgender status or imposing extra fees.

Even post-2017, transgender people are given misinformation about what these policies actually are, said Roem, Virginias first openly transgender lawmaker. Supporters of the bill, including Gray, argue the policy simply codifies federal protections to ensure theyre applied equally to Virginia patients.

But shifting federal guidelines and inconsistent application of the regulations have led opponents to argue that the bill goes farther than other LGBTQ protections by mandating coverage for transition-related medical services. In his testimony against the bill, Jeff Caruso, founding director of the Virginia Catholic Conference, likened the legislation to the 2014 Hobby Lobby case when a Christian-run craft store chain successfully challenged the contraception coverage requirement imposed by the Affordable Care Act.

Due to the tenets of our faith, the health plans of the two dioceses I represent do not cover gender-transition surgeries, he said in an email Tuesday.

Our understanding of the human person is that one has an innate sexual identity that is reflected in the persons biology, he added. Gender reassignment surgeries do not align with this understanding.

Caruso argued that the bill should include a religious exemption, while Josh Hetzler, legislative counsel for the Christian-affiliated Family Foundation of Virginia, opposed the bill entirely.

Were creating a new category of personhood, he argued in his testimony against the bill on Monday. Family Foundation President Victoria Cobb added that the bill set a new precedent by defining gender identity as an internal sense of gender that could include male, female, neither, or a combination of the two.

How can anyone know how to provide medical direction to someone who claims they are an unknown combination of male and female?, she wrote in an email on Tuesday. Why should the insurance company bear the liability to cover unexplored areas of medicine?

Their arguments gained little traction with members of the Senate committee, including Chairman Dick Saslaw, D-Fairfax, who sharply reminded Caruso that the Hobby Lobby ruling was narrowly tailored to apply to contraceptives. Sen. Lionell Spruill, D-Chesapeake who visibly rolled his eyes during the opposing testimony strongly implied that Catholic Church should refrain from criticizing anything on moral grounds in light of the ongoing sexual abuse scandals that have embroiled the church for years.

One church should be the last to say that kind of stuff, given whats going on, he said during Mondays meeting.

They garnered even less sympathy from Roem herself, who said she was unwilling to explicitly deny care for transgender patients under Virginia laws. Advocates argue that the law is especially important given proposed revisions to federal protections, which could roll back nondiscrimination mandates on the basis of sexual identity.

Even with the ACA requirements, health care plans often fail to cover services for transgender patients, said Afton Bradley, care coordination manager for the Virginia League of Planned Parenthoods transgender health care services division.

Afton said roughly a third of VLPPs hormone clinic patients, among those with insurance, were denied coverage by their insurance carriers. Sometimes the denials are based on administrative errors, such as a health plan flagging a prostate exam administered to a patient who identified as female. But Afton said insurers often made it difficult to correct the error during the appeals process, or ended up denying the claim after several weeks of back-and-forth.

Unfortunately, that leads to a lot of our patients paying out of pocket or going without medication, Afton said. And we know that when patients dont have access to transition care, there are serious consequences to their health.

Read the rest here:
Over the objections of religious groups, Virginia is poised to mandate nondiscriminatory care for transgender patients - Virginia Mercury

Recommendation and review posted by Bethany Smith

CHARLOTTE, N.C. On Sunday, March 8, we "spring ahead" by changing our clocks forward one hour for Daylight Saving Time.

But can one hour of lost sleep really impact how we feel? As it turns out, yes, especially if you already struggle to fall asleep at night. Luckily, there are some things experts say you can do to prevent feeling sluggish in the days after the bi-annual time change.

Dr. Harneet Walia of the Cleveland Clinic says people who struggle to get a good night's sleep will feel it the most.

"We, as a society, are already sleep-deprived," Dr. Walia said. "A normal person requires at least seven to eight hours of sleep on a daily basis, and we know that the majority of us don't get that much amount of sleep."

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Luckily, the time change doesn't come as a surprise, so there are things you can do ahead of time to minimize its impact.

"We recommend a few days earlier than the time change is supposed to occur, start going to bed 15 to 30 minutes earlier than your usual time," Dr. Walia said. "That way, your body will adapt, slowly, but surely, when that time change occurs."

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For a good night's sleep, it's best to keep the room dark and avoid looking at devices. Blue light from screens can suppress melatonin, a hormone that regulates sleep. If you're still dragging in the morning, sunshine and caffeine may help.

"We tell people to expose themselves to bright light in the morning. Sunlight is a great thing," Dr. Walia said. "If they're feeling sluggish, caffeine is okay for that day, but not later during the day, because that can then impair their sleep during the nighttime."

Daylight Saving Time officially begins in the Carolinas at 2 a.m. on Sunday, March 8. We will "fall back" to Standard Time on Sunday, November 1.

Read this article:
'Sunlight is a great thing:' Doctor explains how to get over Daylight Saving Time sluggishness - WCNC.com

Recommendation and review posted by Bethany Smith

When I last droned on about car insurance, you may recall I was on the verge of biting the bullet and staying with my current insurer, even though they'd hiked the premium by eight per cent. Instead, I phoned them. The upshot was that they increased my annual mileage allowance by 2,000 miles, extended my policy to cover driving other cars and raised my premium by just 1 a year. Go on, haggle.

Did anybody not see this coming? A 23-year-old started life as a girl, transitioned through surgery and medication to become a man and now, having abandoned hormone treatment, identifies as a woman. She is suing the NHS clinic responsible on the grounds that, as a teenager, she was not challenged enough about her desire to become male. Her lawyers will tell the court that children such as she was cannot give informed consent for such procedures. The clinic says it welcomes this legal examination to clarify things. And so should we all.

Until now, anyone daring to question gender-transition, including medical staff, has been denounced as transphobic by the small but noisy trans-activist lobby. This stifling of dissent may explain why hundreds of young transgender people are now seeking help to return to their original sex. They have been through hell. As this column noted on October 7 last year, While these cases are individual tragedies, the financial outlook for the NHS is terrifying. Five or ten years from now, how many sad transitioned young people will be suing the Department of Health for wrongly advising and treating them?

I got the time-scale wrong. This ethical and financial nightmare is right here, right now and you and I and every other tax payer must foot the bill. (If you resent paying you are, of course, transphobic).

Meanwhile, coronavirus marches on. I am aware, thanks, that it is no laughing matter but doesn't it make you smile just a bit to see a nation preparing to mark the 75th anniversary of VE-Day and to celebrate the courage, resilience, self-sacrifice and community spirit of the wartime generation, while frantically stripping supermarket shelves of tinned food and antiseptic gel?

On the other hand, the wartime generation wasn't composed entirely of angels. I was once researching a book and ploughing through hundreds of back issues of local and national newspapers from 1939-45. I was amazed how many court and tribunal cases involved soldiers deserting from their barracks, civilians refusing to do war work in city factories, publicans watering the booze and plucky Brits fiddling the rations on an industrial scale. The nation that produced heroes like George Mainwaring also produced plenty of spivs like Private Walker.

And if you don't recognise Captain Mainwaring as a hero, then you don't know your Dad's Army.

See the original post:
Peter Rhodes on panic-buying, gender-changing and the not-so-noble side of the Home Front - expressandstar.com

Recommendation and review posted by Bethany Smith

A 17-year-old trans girl has spoken out about the heartbreaking impact of being forced to go through male puberty because she wasnt given access to puberty blockers.

Sonja, a college student in the West Midlands, told the ithat missing out on puberty blockers left her feeling self-conscious, uncomfortable, on the verge of self-harming, suffering from regular panic attacks and struggling to sleep.

I know theres a lot of debate at the moment about hormone blockers and regret but nobody is listening to people like me, Sonja said.

I cant put into words how much I regret nothaving access to blockers and hormones.

Theyre a necessary requirement for me to comfortably live my truth and the fact that Im still not being given that opportunity has such a negative impact on my psychological well-being.

Puberty blockers have been in the news for the past week, since the UKs High Court finally granted permission for a judicial review into whether young transgender people are able to give informed consent to the treatment.

The medication is prescribed to trans teens by specialist gender doctors at the NHSs gender clinic for under 18s, GIDS.

The legal challenge is an attempt to force trans teens to go before a judge before being given medical treatment by doctors.

I think it is important for there to be a judicial review in any system, Sonja said. I do think there are parts that need to be reviewed, like waiting list times.

But the idea being lodged that a person is rushed into taking the blockers and transitioning seems to me a rare occurrence.

I know an exhaustive amount of people who have gone through the system at GIDS.

They wont even approach the issue of puberty blockers until they address a patients preexisting mental health conditions first, and make sure they are making the right decision in a mentally sound state.

Sonja was put on the waiting list for GIDS in November 2017, but two years later was told she was being taken off the waiting list because she wouldnt be seen before her 18th birthday.

In the time she spent waiting for an appointment at GIDS, Sonja went through male puberty and its irreversible effects, which means shell have to undergo invasive surgery to minimise.

The idea of puberty blockers is to halt the natural progression of biological puberty, stop the effects, at least halt the effects of [testosterone] on the body, the enlargement of the Adams apple, the change in muscle density, overall bone structure, and bone growth, she says.

The blockers are taken to pause the onset of puberty while a person contemplates whether or not they want to transition. It means that if they do, they wont have to undergo invasive surgery to remove those characteristics brought about by biological puberty.

Ive had to come to terms with the fact that part of my transition will require significant amount of surgeries, invasive and not. Because the blockers wont put a pause on my puberty, I will enter adulthood tasked with feminising my male characteristics.

To alter from just my neck upwards, theres probably around five facial feminisation surgeries, including the reduction of my jawline, rhinoplasty, and a tracheal shave to reduce the size of my Adams apple. Those surgeries are specifically to remove the effects that male puberty has had on my body.

Mermaids, the charity working with young transgender and gender-diverse people that supports Sonja, has said it may apply to intervene in the High Court case on behalf of the young people it supports.

The Tavistock and Portman NHS Trust, which GIDS falls under, said: We welcome the opportunity to make the case for the quality of care the service provides in a thorough and nuanced way. Our work in GIDS is provided in accordance with best practice and relevant national and international specifications and guidelines.

We are disturbed by the level of misinformation in relation to the support provided to these young people. The often-toxic debate around the topic has caused considerable distress to patients and families. We hope the hearing will serve to set the record straight and put centre-stage the voice and interests of young people living with gender dysphoria.

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Trans teen who waited three years for puberty blockers reveals devastating impact of being denied the treatment - PinkNews

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Dr. Meng-Lun Hsieh and Dr. Andrew Dean Shubin were married March 7 at the Warwick Melrose Hotel in Dallas. The Rev. Beth Dana, a Unitarian Universalist minister, officiated.

The bride, 33, who goes by Meng, is a fourth-year medical school student at Michigan State University, from which she also received a doctorate in biochemistry. She graduated from Williams College.

She is a daughter of Huey-Jen Liaw and Jyh-Cheng Hsieh of San Diego. The brides father is a research scientist at Sheatech, a biotech company in San Diego. Her mother, a stay-at-home parent, was a history teacher at Taibei High School, a private school in Taipei.

The groom, also 33, is a second-year general surgery resident at the University of Texas Southwestern Medical Center in Dallas. He graduated magna cum laude from the University of Washington, and received a doctorate in biomedical engineering from the University of Rochester, from which he also received a medical degree.

He is a son of Carol E. Shubin and Andy N. Shubin of Vancouver, Wash. His father retired as a photography teacher at Shahala Middle School in Vancouver. The grooms mother retired as a special-education teacher at Burton Elementary School in Vancouver.

The couple met a decade ago at the National Institutes of Health in Bethesda, Md., as post-baccalaureate research fellows, she focusing on a virus that infects bacteria, and he on skin stem cells. In April 2016, they met again at a conference for physician scientists in Chicago, and began dating long-distance.

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Meng Hsieh, Andrew Shubin - The New York Times

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For the first time, doctors have used a CRISPR gene editing therapy in an attempt to fix broken genes within the body, marking another step forward for a technology that promises to change how some inherited diseases are treated.

Clinicians at Oregon Health and Science University recently injected the therapy, developed by biotech Editas Medicine and partner Allergan, into the eye of a patient with a type of severe blindness, the companies confirmed Wednesday.

A study last year tested another CRISPR medicine in stem cells extracted from patients' blood, while a third trial previously used a different type of gene editing technology called zinc finger nucleases inside the body. But the patient recently given Editas and Allergan's therapy is the first to be treated using a CRISPR therapy that works in vivo.

The eye disease the companies hope to correct, called Leber cogenital amaurosis, is caused by mutations in any of at least a dozen genes. Editas and Allergan are focusing on just one particular type, known as LCA10. Between 2,000 and 5,000 patients in the U.S. and Europe have it, according to the companies.

"Half of the patients who have this disease are born essentially with light perception vision. They can tell that the room is dark or light," said Mark Pennesi, an associate professor of ophthalmology who is leading OHSU's involvement in the study, in an interview.

"The other half start at legal blindness and then will degrade over the first two decades of life."

Pennesi and his colleagues hope Editas and Allergan's medicine could restore vision by deleting the mutation that prevents the eye from making a protein critical to light-detecting cells.

If that protein is made again, the damaged segment of those photoreceptors should be able to regenerate, said Charles Albright, chief scientific officer at Editas, in an interview last month.

Editas and Allergan plan to enroll 18 adults and children into the study, which is currently being conducted at OHSU as well as centers in Miami, Boston and Ann Arbor, Michigan.

The initial focus will be on safety, as researchers gauge whether the CRISPR medicine being tested causes any side effects or toxicities. Should all go well with the first few adults given a low dose, Editas and Allergan will test four higher doses and potentially try the therapy in children.

Enrolling patients into the study, dubbed BRILLIANCE, has taken longer than the companies first expected when they opened the trial last July.

"Getting patients enrolled and recruiting has taken longer than planned," said Albright, noting there were prospective study participants who came in but ultimately weren't eligible for dosing.

Moving forward, Albright said enrollment should proceed more smoothly.

Whether the treatment helps improve vision will be measured using eye charts and a "mobility maze" similar to one used by Spark Therapeutics for its gene therapy Luxturna, approved in late 2017 for a different type of inherited blindness.

Luxturna works not by editing DNA, but rather by inserting a functional copy of a defective gene directly into the eye. That approach wasn't possible with LCA10, Pennesi said, because the gene in question is too large to fit into the inactivated viruses companies are using as delivery vehicles.

Editing DNA holds potential risks, however the greatest being that the CRISPR therapy inadvertently cuts DNA in places the companies and researchers don't intend and makes irreversible changes.

As with all firsts, the long-term effects of gene editing aren't known either, although Albright noted that photoreceptor cells in the eye no longer divide, potentially making the results of Editas and Allergan's therapy more predictable.

While Editas and Allergan are first to the milestone of in vivo CRISPR editing, the field around them is quickly advancing.

CRISPR Therapeutics and Vertex, which are running the study that used a CRISPR therapy on extracted stem cells, already have initial data, while rival Intellia Therapeutics plans to begin this year a study of in vivo CRISPR editing in a rare disease known as transtheyretin amyloidosis.

Other, newer companies, meanwhile, are working to move past CRISPR and into more specific types of gene editing. One, the Cambridge, Massachusetts-based Beam Therapeutics, recently raised $207 million on the promise of its base-editing platform.

But the studies run by CRISPR Therapeutics and Editas, being the first in their respective settings, will be watched close.

"These are setting precedent," said Albright. "You're going to be seeing a lot more gene editing."

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In a CRISPR first, Editas therapy used to fix genes in the body - BioPharma Dive

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INTRODUCTION

An efficient gene drive could rapidly modify or suppress a target population (14). Such a mechanism could potentially be used to prevent transmission of vector-borne diseases such as malaria or dengue and could also have conservation applications (14). The best-studied form of an engineered gene drive mechanism is the homing drive, which uses the CRISPR-Cas9 system to cleave a wild-type allele. The drive allele is then copied into the wild-type site via homology-directed repair, increasing the frequency of the drive allele in the population. Thus far, CRISPR homing gene drives have been demonstrated in yeast (58), flies (916), mosquitoes (1719), and mice (20).

However, homing drives typically suffer from high rates of resistance allele formation. These alleles can form when DNA is repaired by end joining, which often mutates the sequence. The consequence of a changed sequence is that the drives guide RNA (gRNA) can no longer target the allele for cleavage. Resistance alleles have been observed to arise both in germline cells as an alternative to homology-directed repair and in the early embryo due to deposition of Cas9 and gRNA into the egg by drive-carrying mothers (12). While formation of resistance alleles remains the primary obstacle to construction of efficient gene drives, substantial progress has been made toward overcoming this challenge. For example, a suppression-type drive in Anopheles gambiae (21) and a modification-type drive in Drosophila melanogaster (16) avoided issues with resistance alleles by targeting an essential gene. Because of this, resistance alleles that disrupted the function of the target gene had substantially reduced fitness. This allowed both drives to successfully spread through cage populations.

Multiplexing gRNAs has been proposed as a mechanism for increasing the efficiency of gene drives (1, 4). This would purportedly work by two mechanisms. First, having multiple cut sites would potentially allow drive conversion even if some of the sites have resistance sequences due to previous end joining repair at those sites. As long as at least one site remains wild type and, thus, cleavable, homology-directed repair can still occur. Second, the chance of forming a full resistance allele that preserves the function of the target gene would be substantially reduced due to the possibility of disruptive mutations forming at any of the gRNA target sites. Resistance alleles that disrupt the function of the target gene incur large fitness costs in several drive designs, which would make resistance substantially less likely to block the spread of the drive.

However, two studies using two gRNAs (13, 16) showed somewhat lower increases in efficiency than predicted by simple models of multiple gRNAs (2224). This is partially because most models assume that cleavage and repair by either homology-directed repair or end joining occurs sequentially at each gRNA target site. However, it appears that some germline resistance alleles form before the narrow temporal window for homology-directed repair (10, 12, 13). Additional resistance sequences may also form as a direct alternative to successful homology-directed repair, while others could form after meiosis I when only end joining repair is possible. Furthermore, unless cleavage occurs in both of the outermost gRNA target sites during the window for homology-directed repair, the wild-type chromosome on either side of the cleavage would have imperfect homology to the drive allele because of nonhomologous DNA between the cut site and the homology arm (13). Imperfect homology likely reduces repair fidelity (i.e., less homology-directed repair and more end joining repair). This proposition is supported by the greatly reduced efficiency seen in a construct with four gRNA targets located far apart from one another (9). Last, it is unlikely that gRNAs are the limiting factor in Cas9/gRNA enzymatic activity (15). As the number of gRNAs increases, the total cleavage rate likely plateaus, thus reducing the cleavage rate at each individual site and thereby preventing further gains in drive efficiency.

Here, we systematically model these factors and show how they are expected to affect the performance of homing drives with multiple gRNAs. We verify and parameterize these models via experimental analysis of several homing drives in D. melanogaster. We additionally consider other factors that could reduce gene drive performance, such as partial homology-directed repair and uneven activity of gRNAs. We then apply our model to predict drive performance in Anopheles mosquitoes, assessing several types of homing drives for population modification or suppression. We find that the reduction in efficiency due to imperfect homology is synergistic, with the lower per-site cleavage rates from Cas9 activity saturation. Because of this, each type of drive has an optimal number of gRNAs that results in maximized overall performance, a finding that could inform future designs of homing gene drives.

In our model, we consider five types of homing gene drive systems:

1) Standard drive. The standard homing drive is a population modification system. Its primary drive mechanism occurs in germline cells during early meiosis. When it operates successfully, the drive allele replaces wild-type alleles in the germline. However, resistance alleles can also form, preventing the spread of the drive.

2) Population suppression drive. This drive increases in frequency in the same manner as the standard homing drive, and resistance alleles develop under the same circumstances. However, the drive targets a recessive female fertility gene and disrupts the function of the gene with its presence. Resistance alleles can also disrupt the function of the target gene. Females with two disrupted copies of the gene are rendered sterile, while males are unaffected. Notably, unlike the standard homing drive, this drive does not carry any payload, as, it accomplishes its goal simply with its presence. Such a drive was successful in laboratory populations of the mosquito A. gambiae (21).

3) Haplolethal drive. This drive system is a modification of the standard homing drive system. It targets a gene that is critical to the viability of the individual. However, the drive contains a recoded portion of the gene that is immune to Cas9 cleavage, so the presence of the drive does not disrupt the function of the target. If an individual receives a resistance allele that disrupts the haplolethal target, then that individual will not be viable, preventing these resistance alleles from entering the population. A haplolethal homing drive was successful in a laboratory population of the fruit fly D. melanogaster (16).

4) Recessive lethal drive. This drive is similar to the haplolethal drive, but the target is recessive lethal. Only individuals carrying two resistance alleles that disrupt the target gene function are nonviable. Thus, resistance alleles are removed from the population more slowly. However, this drive may be easier to engineer because the drive can provide rescue even in the presence of a resistance allele. It is also more tolerant of a high rate of embryo resistance allele formation because this allows it to operate better as a toxin-antidote system (25, 26).

5) Gene disruption drive. The gene disruption homing drive is a population modification system that is similar to the suppression drive in that its presence disrupts the target gene, as do resistance alleles. However, individuals with two disrupted copies of this gene remain viable and fertile, although they suffer from a small additional fitness cost. The purpose of this drive is to remove the functionality of a particular gene from the population, which can provide benefits such as reduction in disease transmission (27, 28). An advantage of this drive is that there is no need for a recoded sequence. However, finding suitable targets for particular applications could potentially be difficult.

We implemented each of the gene drive models using SLiM version 3.2.1 (29). SLiM is an individual-based, forward-time population genetic simulation framework. General parameters and ecology components are shared across all models.

Our model considers a single panmictic population of sexually reproducing diploid individuals with nonoverlapping generations. The model differs from a standard Wright-Fishertype model in that population size is not regulated. Offspring are generated from random pairings throughout the population, with mate choice and female fecundity affected by genotype fitness. To determine mate choice, first, a random male is selected. This candidate is then accepted at a rate equal to his genotype fitness (e.g., a male with a fitness of 0.5 is accepted half of the time). If he is rejected, then another random candidate is selected, until either a mate has been chosen or the female fails to find an acceptable mate after a total of 10 attempts. Female fecundity is then multiplied by her genotype fitness, along with a factor representing the impact of population density in the system: 10/(1 + 9 N/K), where N is the total population and K is the carrying capacity. A number of offspring are then generated on the basis of a binomial distribution with a maximum of 50 and p = fecundity/25. This model produces logistic dynamics while allowing the population size to fluctuate around the expected capacity. After pairings and offspring have been determined, the genotypes of the offspring are modified according to the genetic component of the model.

In one set of simulations, a small number of drive/wild-type heterozygous flies were introduced into a wild-type population of 100,000 at an initial frequency of 1%. The simulation was then conducted for 100 generations. In another set of simulations, a wild-type female was crossed to a drive/wild-type heterozygote male, and a configurable number of offspring were generated from that single pairing. The genotype of each offspring was recorded to estimate drive performance parameters. Drive conversion was equal to the fraction of wild-type alleles in the germline converted to drive alleles, and resistance allele formation rates also represented rates of conversion from wild-type alleles. The genetic module of our model is described in the Supplementary Methods.

Detailed descriptions of our plasmid construction techniques, the construction and sequencing primers used, the generation of transgenic lines, fly rearing, phenotyping and analysis techniques, and genotyping are available in the Supplementary Methods.

To compare our results to previous work, we constructed a simple model of homing drive dynamics. This model considers each gRNA site independently, with parameters inspired by highly efficient homing drives in Anopheles mosquitoes (18, 19, 21, 30). At each gRNA target site, we assume a cut rate of 99%. If the site is cut, then there is a 7.8% chance that a resistance sequence will be formed. Otherwise, homology-directed repair occurs, and the entire allele (including all target sites, even if some have resistance sequences) is converted to a drive allele. In this model, increasing the number of gRNA target sites always increases the efficiency of the drive, and arbitrarily low resistance rates can be achieved by adding more target sites (Fig. 1). Since even relatively few gRNAs can reduce resistance allele formation to very low levels under this model, gRNA multiplexing has been considered as a highly promising and comparatively straightforward method to avert resistance in homing gene drives (2224).

Five million offspring were generated from crosses between drive/wild-type heterozygotes and wild-type individuals for each model and number of gRNAs. The rate at which wild-type alleles are converted to resistance alleles in the germline of drive/wild-type heterozygous individuals is shown.

The simple model does not take timing of cleavage and repair into account. However, several lines of evidence indicate that cleavage timing can play a key role in drive conversion. Experiments indicated that wild-type alleles can only be converted to resistance alleles and not to drive alleles in the early embryo due to maternally deposited Cas9 (12, 13), where homology-directed repair for the purposes of drive conversion does not take place at appreciable rates. Furthermore, at least some resistance alleles form in pregonial germline cells that can affect the genotype of multiple offspring (10, 12, 13). After the chromosomes separate in late meiosis, homology-directed repair is no longer possible, and any cleavage at this time results in the formation of resistance alleles by end joining repair. It is thus likely that there is only a narrow temporal window in the germline, during which the drive can be successfully copied via homology-directed repair. This window presumably covers early meiosis when homologous chromosomes are close together, which would increase the chance that one chromosome could be used as a template for repair of a double-strand break in the other.

To explore the expected impact of these mechanisms on resistance rates, we constructed a model where cuts during a homology-directed repair phase occur simultaneously, and the DNA then has a single opportunity to undergo homology-directed repair. In this model, there are discrete temporal phases. In each phase, wild-type gRNA sites are cut before any repair takes place. In the first phase, end joining repair always occurs after cutting, so having more gRNAs allows more target sites to avoid being converted to resistance alleles. Only in the next phase is homology-directed repair possible, which takes place at a specific rate if any cutting occurs. If homology-directed repair (successful drive conversion) does not take place, then end joining is assumed to repair the cut, forming a resistance allele. Thus, as the probability of the DNA being cut approaches 100% due to many gRNAs, the overall rate of resistance formation does not decrease indefinitely. Instead, it reaches a minimum value equal to the chance that end joining takes place instead of successful homology-directed repair in the second phase (Fig. 1). This suggests that the simple model of multiple gRNAs is likely inadequate to accurately assess homing drive dynamics.

Previous experiments with two gRNAs resulted in a lower-efficiency improvement than even that predicted by our model that included timing (13). This was shown even more starkly with a four-gRNA drive (9) that had a lower drive conversion efficiency than a one-gRNA drive. We hypothesize that two additional factors could account for this discrepancy. First, the rate at which homology-directed repair occurs after cleavage in the appropriate phase (which we refer to as repair fidelity) is likely reduced if the DNA on either side of the cut sites does not have immediate homology to the drive (meaning that end resection must proceed for several nucleotides before it reaches DNA with homology to the drive). This will often be the case because a drive allele is constructed to have DNA homologous only to that at the outermost cut sites (the leftmost and rightmost sites). Thus, drive efficiency is reduced except when both outer gRNAs are cleaved. Second, the amount of Cas9 enzyme is limited. Thus, as the number of gRNAs increases, Cas9 eventually becomes saturated with gRNAs and cleavage activity plateaus. This has the effect of decreasing the cleavage rate at individual gRNA sites as the total number of gRNAs increases. To test the impact of these two mechanisms on drive efficiency, we conducted a series of experiments.

We first constructed a drive system in D. melanogaster that targeted a synthetic enhanced green fluorescent protein (EGFP) site with one gRNA and Cas9 driven by the nanos promoter (fig. S1), similar to previous synthetic target site drives (15). Drive/wild-type heterozygotes displayed a drive conversion efficiency of 83% [95% confidence interval (CI), 79 to 86%] in females and 61% (95% CI, 57 to 65%) in males (data S1). These values were higher than previous synthetic target site drives (15), likely due to the different genomic location of the target site or the different gRNA target, which targeted further away from the 3xP3 promoter in EGFP. Drive conversion efficiency was significantly higher in females (P < 0.0001, Fishers exact test), which was consistent with previous studies (13, 15). It remains unclear why this may be the case, but it may be due to sex differences in levels of repair proteins in the germline (possibly related to the lack of male chromosomal recombination), resulting in a higher ratio of homology-directed repair to end joining in the appropriate temporal window. Expression of Cas9 by the nanos promoter could also be variable between the sexes. If expression started earlier in males, then an increased number of resistance alleles could form before the temporal window for homology-directed repair.

Since multiplexing of gRNAs can best be accomplished by expressing them from a single compact promoter, we modified our drive system to include a transfer RNA (tRNA) that must be spliced out of the gRNA gene to generate an active gRNA. By including additional tRNAs between gRNAs, several gRNAs can be expressed together with this system (31). We found that drive/wild-type heterozygote females had a drive conversion efficiency of 82% (95% CI, 78 to 86%) in females and 65% (95% CI, 62 to 70%) in males for the one-gRNA drive with the tRNA (data S2). This indicates that the tRNA system functions correctly in homing drives without apparent loss of efficiency, allowing its use in multiplexed gRNA experiments.

We next constructed a drive to determine the effects of reduced homology between the cleaved wild-type chromosome and the drive allele. We used a single gRNA as above with the tRNA system but with the right homology arm realigned to a hypothetical second gRNA cut site (Fig. 2). Thus, the first 114 nucleotides to the right of the cut site would not be homologous to any DNA around the drive allele. Drive conversion rates for females were only 84% (95% CI, 77 to 90%) of the rate of the one-gRNA drive that had full homology around the cut site, while the rate for males was 89% (95% CI, 83 to 96%) of the full homology drive (data S3). This indicates that a multiple-gRNA drive would indeed exhibit lower conversion efficiency when cleavage does not take place at both ends.

Blue shows gRNA target sites, and black shows regions of DNA that have no homology to the drive allele. Highly active gRNAs are shown by a red lightning bolt, and gRNAs with low activity are shown with an orange line icon.

To assess the effects of Cas9 activity saturation, we examined three constructs containing Cas9 with either zero, one, or four gRNAs targeting a genomic region located between two genes and downstream of both to minimize potential interference with native genes. Mutations resulting from the repair of cleavage events in this area are thereby unlikely to affect an individuals fitness. These constructs were placed at the same genomic site as the synthetic target site constructs. Individuals with these constructs were crossed to those carrying the split drive targeting yellow developed previously (15) to generate individuals heterozygous for both a Cas9 element and a split-drive element. These individuals all had a single gRNA targeting yellow and a variable number of gRNAs that target a region where sequence changes produce no phenotype. The embryo resistance allele formation rates in individuals with zero, one, or four gRNAs that were not targeting yellow in the Cas9 element were 83% (95% CI, 80 to 87%), 72% (95% CI, 68 to 77%), and 65% (95% CI, 60 to 70%), respectively (data S4). The differences between the construct with zero additional gRNA elements and the others were statistically significant (P < 0.0001 in both cases, Fishers exact test), although the difference between the constructs with one and four additional gRNAs did not quite reach statistical significance (P = 0.06, Fishers exact test). The amount of the gRNA targeting yellow was constant in these drives. However, the rate at which yellow was cleaved decreased as the number of other gRNAs increased. This is consistent with the hypothesis that saturation of Cas9 activity reduces the cleavage rates at individual gRNA target sites when the total number of gRNAs is increased.

Nevertheless, Cas9 does not necessarily become fully saturated with a single gRNA. The total cleavage rate could potentially somewhat increase if additional gRNAs are provided, although it would likely plateau rapidly. When heterozygotes for the split drive targeting yellow (15) and the standard drive targeting yellow (12) (which had one copy of Cas9 and two copies of the gRNA gene) were crossed to w1118 males, the rate of embryo resistance allele formation and mosaicism was somewhat higher than for standard drive/resistance allele heterozygotes with one copy of Cas9 and only one gRNA gene (P = 0.0036, Fishers exact test) (data S5).

To assess the performance of drives with multiple gRNAs, we created several additional constructs targeting EGFP, but with two, three, or four gRNAs (Fig. 2). The left target site for each of these was the same as for the one-gRNA synthetic target site drives, and the homologous ends of all of these drives matched the left and right gRNA target sites. However, we found that of the four gRNAs used, only the first and the third had high cleavage activity, as indicated by sequencing of embryo resistance alleles (table S1). Although germline cleavage activity was likely somewhat higher than in the embryo for these gRNAs, their low activity undoubtedly reduced drive performance. Nevertheless, we found that the overall performance of these drives was consistent with the performance predicted by our model that included the effects of timing, repair fidelity, and Cas9 activity saturation (Fig. 2). The results show that adding additional gRNAs does not exponentially increase the efficiency of homing drives.

Specifically, we constructed two different two-gRNA drives. One of these had two closely spaced gRNA targets (36 nucleotides apart) and showed a drive conversion efficiency of 78% (95% CI, 74 to 83%) in females and 62% (95% CI, 56 to 67%) in males (data S6). This was slightly higher than the second drive where the two gRNAs were more widely spaced (114 nucleotides apart), which demonstrated a drive conversion efficiency of 74% (95% CI, 70 to 79%) in females and 60% (95% CI, 55 to 64%) in males (data S7). Because the second gRNA has low activity in each of these drives, the small difference in the performance between them could possibly be accounted for by the lower repair fidelity in the drive with more widely spaced gRNAs (Fig. 2) when only one target site is cut. The drive with three gRNAs was similar to the two-gRNA drive with widely spaced gRNAs, with the addition of a third active gRNA in between the two target sites of the two-gRNA drive. This likely increased the overall cleavage rate due to the higher proportion of active gRNAs and allowed for greater repair fidelity on the right end, since cleavage in this system usually takes place at the left and middle gRNA targets, instead of often only at the left gRNA target. Thus, this construct showed an improved drive conversion efficiency of 80% (95% CI, 77 to 84%) in females, although male drive conversion efficiency apparently remained at 60% (95% CI, 56 to 64%). A final construct added an additional gRNA between the left and middle gRNAs (the same gRNA that the closely spaced two-gRNA construct included). However, since this gRNA had low activity, overall drive performance may have been negatively affected by saturation of Cas9 by gRNAs, resulting in a reduced drive conversion efficiency of 73% (95% CI, 69 to 76%) in females, although male drive conversion efficiency appears to have improved to 65% (95% CI, 61 to 68%) (possibly due to an underestimation of conversion efficiency for males with the three-gRNA construct).

To further refine our model, we next incorporated distinct phases for homing drive dynamics in the germline (Fig. 3). In this model, we assume that first, early germline resistance alleles form, followed by a homology-directed repair phase, and then a late germline resistance allele formation phase. In the embryos of mothers with at least one drive allele, maternally deposited Cas9 and gRNA can result in the formation of additional resistance alleles. During this process, deletions can occur if cleavage occurs nearly simultaneously at different cut sites. If a second site is cleaved before a first cleavage has been repaired, then the section of DNA between the two sites is excised when the gap is closed by end joining repair.

First, wild-type gRNA target sites can be cleaved in the early germline, forming resistance alleles. Next, cleavage occurs at a high rate in the homology-directed repair phase. Usually, this results in successful conversion to a drive allele. However, if homology-directed repair fails to occur, then end joining can form resistance alleles. Incomplete homology-directed repair can also convert the entire allele to a resistance allele, ignoring individual target sites. Next, another resistance allele formation phase converts most remaining wild-type sites into resistance sequences. Meiosis and fertilization take place, and then, if the female parent had at least one drive allele, a final phase of resistance allele formation takes place in the early embryo.

We additionally model reduced repair fidelity from imperfect homology around the cut sites, Cas9 activity saturation, and variance in the activity level of individual gRNAs. See the Supplementary Results for a detailed treatment of these model components and estimation of parameters based on our experiments. Models with repair fidelity or Cas9 activity saturation alone did not produce much deviance from our basic model with timing (Fig. 4). However, a model that includes both repair fidelity and Cas9 activity saturation demonstrated fundamentally changed dynamics. We found that there was a synergistic effect between the factor of the reduced cut rate per site caused by Cas9 activity saturation and the factor of reduced repair fidelity when the outermost target sites are not cut. Because of this, we find the emergence of an optimal number of gRNAs to maximize drive conversion efficiency (Fig. 4), which decreases rapidly when additional gRNAs are added. The additional modeling of gRNA activity variance had only a small negative effect on drive conversion performance (Fig. 4).

Five million offspring were generated from crosses between drive/wild-type heterozygotes and wild-type individuals for each model and number of gRNAs. The rate at which wild-type alleles are converted to drive alleles in the germline of drive/wild-type individuals is shown.

With parameters simulating an efficient A. gambiae construct, the optimal number of gRNAs in this model is two, although drives with three gRNAs have nearly as good conversion efficiency (Fig. 4). Thus, not only do further increases in the number of gRNAs fail to provide substantial benefits, they actually result in substantial reductions in drive efficiency. However, note that the optimal number of gRNAs for overall performance may be somewhat greater than the optimal number for drive conversion efficiency, as detailed below.

Resistance alleles can either preserve or disrupt the function of a target gene. The latter are expected to be more common due to frameshift mutations or other disruptions to the target sequence but should usually be less detrimental to drive performance. In our model, we assume that resistance sequences preserving the function of the target gene form in 10% of cases (12, 13), although this could be substantially reduced by targeting conserved sequences (13, 16, 21). We further assume that if even a single resistance sequence that disrupts the function of the target gene is present, the target gene is rendered nonfunctional. Any deletion due to simultaneous cleavage followed by end joining repair is also assumed to disrupt the target gene. One major advantage of multiple-gRNA drives is therefore that complete resistance alleles that preserve the function of the target gene should become exponentially less common as the number of gRNAs increases (Fig. 5, black line).

Five million offspring were generated from crosses between drive/wild-type heterozygotes and wild-type individuals for each number of gRNAs and each level of probability that incomplete homology-directed repair results in the formation of resistance alleles that preserve the function of the target gene. The formation rate of resistance alleles that preserve the function of the target gene is shown. No such resistance alleles were formed in systems with at least four gRNAs, except in drives where incomplete homology-directed repair was possible.

However, certain types of gene drives are vulnerable to incomplete homology-directed repair as another mechanism for forming resistance alleles that preserve the function of the target gene. These drives target a critical gene such that individuals are rendered nonviable if one (haplolethal) or both (recessive lethal) alleles are disrupted. The drives contain a recoded sequence of the targeted gene that is immune to cleavage by the drives gRNAs. If homology-directed repair copies the recoded portion of the drive, a complete resistance allele that preserves the function of the target gene is formed, regardless of the number of gRNA targets in the system. For modification drives, this is not an issue if the payload is also copied. These events are likely to be even more rare than copying of only the rescue element (because the rescue element is often located at the end of a drive). It is similarly unlikely for the rescue and drive elements to be copied without the payload. Thus, the only outcome of incomplete homology-directed repair that we model is full resistance formation, either disrupting or, more rarely, preserving the function of the target gene. A more detailed discussion of this mechanism is provided in the Supplementary Results covering incomplete homology-directed repair. With incomplete homology-directed repair as the last element in our full model, we find that there is an optimal number of gRNAs for this family of drives for minimizing resistance alleles that preserve the function of the target gene. This number is usually three, but it is somewhat higher when the rate of incomplete homology-directed repair copying the recoded region is very low (Fig. 5).

With our full model in place, we consider the performance of several types of drives. The first of these is the standard homing drive. This drive accomplishes its goal by carrying an engineered payload and targets a neutral locus. Consequently, there is no effect from disrupting the target, and all resistance alleles are treated the same. The next is a suppression drive targeting a recessive female fertility gene (21). In this drive, females are rendered sterile unless they have at least one wild-type allele or a resistance allele that preserves the function of the target gene. The dynamics of this drive result in complete population suppression when it is successful. We also consider approaches for population modification that target a haplolethal or recessive lethal gene, where the drive has a recoded sequence of the gene that is immune to gRNA cleavage (16). In the haplolethal approach, any individual with a resistance allele that disrupts the target gene is nonviable, removing these alleles from the population. In the recessive lethal approach, an individual is only nonviable if it has two such resistance alleles. Last, we consider a population modification drive that targets a gene of interest, such as a gene required for malaria transmission in Anopheles (27, 28). Rather than carrying a payload, this drives purpose is to disrupt its target in a manner similar to that of the suppression drive.

We found that the optimal number of gRNAs for the population modification drives to achieve a maximum drive frequency was three, although drives with two gRNAs were nearly as efficient (Fig. 6A). The haplolethal drive reached nearly 100% frequency when modeled with two or more gRNAs (Fig. 6A) due to rapid removal of resistance alleles. The recessive lethal drive is slower at removing resistance alleles when they form at low rates, so it reached a lower frequency (Fig. 6A). However, the haplolethal drive also removes drive alleles when they are present in the same individual as a resistance allele that disrupts the function of the target gene. Thus, this system spreads somewhat more slowly than other types of population modification drives, although not as slowly as the population suppression homing drive (Fig. 6B). Of particular interest, gRNAs beyond two reduce drive conversion efficiency, which results in a slower spread of the drive (Fig. 6B). However, having multiple gRNAs is essential for reducing the formation rate of resistance alleles that preserve the function of the target gene (Fig. 5), which would otherwise outcompete drive alleles over time (Fig. 6C).

Drive/wild-type heterozygotes were released into a population of 100,000 individuals at an initial frequency of 1%. The simulation was then conducted for 100 generations using the full model. The displayed results are the average from 20 simulations for each type of drive and number of gRNAs. (A) The maximum drive allele frequency reached at any time in the simulations. Note that the standard drive and gene disruption drive have nearly identical values. (B) Number of generations needed for the drive to reach at least 50% total allele frequency. Note that the suppression drive is only shown in (B). (C) Final frequency of resistance alleles after 100 generations. The displayed values are only for resistance alleles that preserve the function of the target gene. No resistance alleles were present in the standard drive and gene disruption drive when at least four gRNAs were present. (D) Final effector allele frequency in the population after 100 generations. This was the drive allele for most drive types, but for the gene disruption drive, it includes resistance alleles that disrupt the function of the target gene as well.

Overall, having three gRNAs is usually optimal for population modification drives to attain maximum drive frequency after 100 generations (Fig. 6D). However, for the gene disruption homing drive, the optimal number of gRNAs for maximizing the frequency of effector alleles was four, five, or six (Fig. 6D). This is because effector alleles for this drive also include resistance alleles that disrupt the function of the target gene. In addition, this type of drive is not substantially impaired by incomplete homology-directed repair. This means that gene disruption drive can make efficient use of a higher number of gRNAs. Drives modeled with somewhat reduced performance based on our Drosophila experiments in this study (albeit with slightly lowered embryo resistance allele formation rates to represent an improved promoter) showed similar patterns, but with the optimal number of gRNAs increased by one for each drive (fig. S5 and see the Supplementary Results).

Suppression-type homing drives are particularly prone to failure if the resistance allele formation rate is high or if the drive conversion efficiency is too low. When examining the rate at which the drive was successful in completely suppressing the population (Fig. 7A), our high-performance drives with default parameters were usually successful, so long as there were sufficiently many gRNAs. However, drives with somewhat reduced performance (see the Supplementary Results) were less able to achieve successful suppression, regardless of the number of gRNAs. As with the default parameters, low numbers of gRNAs resulted in formation of resistance alleles that preserved the function of the target gene, which were able to quickly reach fixation in the population and prevent suppression (Fig. 7B). With an intermediate number of gRNAs, complete population suppression still usually occurred (Fig. 7C), but when the number of gRNAs was high, the rate of complete suppression declined. This is because with a high number of gRNAs, the drive suffered from reduced conversion efficiency and lacked the power to completely suppress the population (Fig. 7D). As the number of gRNAs is increased beyond two to three, the genetic load imposed by the drive at its final equilibrium (in the absence of resistance alleles that preserve the function of the target gene) is substantially reduced (fig. S6), preventing the drive from inducing complete suppression if the population growth rate at low densities is sufficiently high. With a choice of target sites with reduced formation of resistance sequences that preserve the function of the target gene, complete suppression becomes more likely, and the optimal number of gRNAs is reduced (fig. S7).

Drive/wild-type heterozygotes with a suppression drive were released into a population of 100,000 individuals at an initial frequency of 1%. The simulation was then conducted for 100 generations. (A) The displayed results are the average from 20 simulations for each type of drive and number of gRNAs. The fraction of simulations that resulted in complete suppression is shown. The full model was used. The default system based on the Anopheles parameters used an early germline cleavage rate of 2%, a homology-directed repair phase cleavage rate of 98%, and an embryo cleavage rate of 5%. For the reduced efficiency drive model, these parameters were changed to 5, 92, and 10%, respectively. The low efficiency drive model changed these parameters to 8, 90, and 15%, respectively. Allele frequency and population size trajectories are shown for individual simulations using the reduced efficiency model with (B) 2, (C) 4, and (D) 10 gRNAs. r1 refers to resistance alleles that preserve the function of the target gene, and r2 refers to resistance alleles that disrupt the function of the target gene.

Our study shows that homing drives likely have an optimal number of gRNAs that maximize drive efficiency while minimizing the formation of resistance alleles that preserve the function of the target gene. This result emerged naturally from a model that incorporated specific time steps for cleavage and repair, Cas9 activity saturation, and reduced repair fidelity when homology ends around the cut sites fail to line up perfectly. Even with a more basic model that differs from the model only by allowing a narrow timing window for homology-directed repair, we are able to reject the notion that homing gene drives can be made arbitrarily efficient by having a sufficiently high number of gRNAs. Overall, we showed that while multiple gRNAs are useful for improving drive efficiency and reducing resistance, these performance gains are far smaller than those predicted by simple models with sequential cutting and repair (2224) or even models that include simultaneous cutting (22). This new model is consistent with our experimental results in this study, as well as previous work that observed smaller improvements from multiple gRNAs than predicted (13) or even marked declines in performance (9). Our model also takes germline cleavage timing into account, which is consistent with resistance allele sequencing in previous experimental studies (10, 12, 13).

While our model represents a step forward in our understanding of how multiplexed gRNAs affect homing drive efficiency, further improvements are needed to be able to more accurately predict homing drive performance. Earlier work indicated that the window for homology-directed repair is narrow, with only resistance alleles forming before and afterward (10, 12, 13). A better understanding of this window, the rate of successful homology-directed repair, and the proportion of resistance alleles formed before, during, and after this window would allow for improvements to our model. Homology of DNA on either side of a cut site is well known to be critical for the fidelity of homology-directed repair, and we showed that it indeed influences drive conversion efficiency. Last, Cas9 cleavage activity always reaches a maximum as more gRNAs are added, although details of this have not yet been thoroughly quantified. It is likely that for many gRNA promoters, a maximum cut rate would be reached quickly, thus reducing the cleavage rates at individual gRNA target sites as the total number is increased. Future studies could investigate how this saturation occurs and enable refinement of the quantitative model. In particular, the rate of resistance alleles formed due to incomplete homology-directed repair could be better quantified, with particular attention paid to the rate at which any recoded region is fully copied, thereby forming a resistance allele that preserves the function of the target gene. Last, variance in the activity level of gRNAs is well known, and we also observed this in our multiple gRNA homing drives in this study. These activity levels could potentially be predicted (32), but experimental assessment will likely remain necessary in the foreseeable future.

In our model, we also assumed that each gRNA cut site independently had the same chance of forming a resistance sequence that disrupts the function of the target gene. Thus, gRNA target sites would be best located close together to maximize repair fidelity. In practice, frameshifts between gRNA cut sites, but with restored frame after the last mutated site, may be insufficient to disrupt the function of the target gene. Thus, a good practice to minimize the formation of resistance alleles that preserve the function of the target gene would be to target conserved or important regions less tolerant of mutations, and perhaps to space gRNAs far enough apart, despite the cost to drive conversion efficiency, to ensure that a frameshift between any two gRNA sites disrupts the gene. At minimum, gRNAs should be placed far enough apart to prevent mutations at one site from converting an adjacent target site into a resistance allele.

Our models allowed us to gain insights about the relative strengths and weaknesses of the different types of homing gene drives. Standard drives lack any particular mechanism for removing resistance alleles (they need not even target a specific gene), which means that a successful drive of this nature requires a high drive efficiency, very low resistance allele formation rates, and low fitness costs to persist long enough to provide substantial benefits. The optimal number of gRNAs for these drives is likely low, perhaps two or three for a highly efficient system.

By contrast, drives that target haplolethal or recessive lethal genes can effectively remove resistance alleles that disrupt the function of the target gene and, thus, tolerate substantially higher overall rates of resistance allele formation. These drives are not expected to lose much efficiency with larger numbers of gRNAs, because although drive conversion efficiency is reduced, the drives also operate by toxin-antidote principles (25, 26), enabling removal of wild-type alleles and an accompanying relative increase in drive allele frequency even without drive conversion. However, we hypothesize that with reduced homology around the cut sites, incomplete homology-directed repair becomes more likely. This results in an optimal level of gRNAs that minimizes the formation of resistance alleles that preserve the function of the target gene due to incomplete homology-directed repair and end joining mechanisms. It is unclear how often incomplete homology-directed repair occurs, but it is likely that the optimal number of gRNAs for these drives is perhaps three or four. However, the rate of incomplete homology-directed repair could perhaps be minimized if the drive is located in an intron (possibly a synthetic intron), with essential recoded regions on either side of the intron. A system of this nature would only form a resistance allele that preserves the function of the target gene if incomplete homology-directed repair were to occur on both sides of the drive. This would allow for efficient use of a greater number of gRNAs. Improvements of this nature may not be necessary, however, if the rate of resistance allele formation that preserves the target function is substantially less than the rate at which payload genes are inactivated by mutations that occur during homology-directed repair (106 per nucleotide), which is approximately 1000-fold greater than the rate by DNA replication. If such a rate would preclude effective deployment of a homing drive, then toxin-antidote systems (25, 26) that rely only on DNA replication for copying of payload genes may be more suitable.

A gene disruption homing drive for population modification could potentially avoid both the need for a recoded region and inactivation of payload genes by targeting an endogenous gene. In this case, the end goal would be to disrupt this gene either by the presence of the drive or by formation of resistance alleles, rather than spreading a specific payload, and the formation of resistance alleles that disrupt the target gene may actually be beneficial due to their reduced fitness cost compared to the drive. For such a drive, the optimal number of gRNAs would be the minimum number necessary to prevent the formation of resistance alleles that preserve the function of the target gene, perhaps four to eight, depending on population size, target site, and drive performance.

A drive designed for population suppression has similar considerations, but with a narrower window for success. This is because any formation of complete resistance alleles that preserve the function of the target gene would likely result in rapid failure of the drive. In addition, if drive conversion efficiency is insufficient, then the drive may lack the power to completely suppress the population, at least within a reasonable timeframe. Thus, a narrower range of five to seven gRNAs would likely be optimal for such a drive. For all of these drive types, if the rate of resistance allele formation that preserves the function of the target gene is lower than in our models (such as by targeting a sequence that is highly intolerant of mutations (21)), then the optimal number of gRNAs is somewhat reduced.

Overall, we conclude that the total number of gRNA should be kept relatively low to achieve maximum effectiveness of multiple-gRNA drives: at least two, but well under a dozen, with the exact number depending on the type of drive and other performance characteristics. The gRNA target sites should also be placed as close together as possible while still far enough apart to prevent mutations at one target site from affecting adjacent sites. While our results suggest that multiplexing of gRNAs alone is unlikely to enable the development of highly effective homing drives, we expect that this approach will still be a critical component of any successful drive, especially when combined with additional strategies.

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Computational and experimental performance of CRISPR homing gene drive strategies with multiplexed gRNAs - Science Advances

Recommendation and review posted by Bethany Smith

Ebola. Sickle cell disease. Spinal muscular atrophy. Cystic fibrosis.

Everyone agrees the void is a problem, but theres little consensus on how to tackle it and theres no panacea to speak of.

Behind each disease was a medical breakthrough that Francis Collins highlighted at the congressional hearing on the presidents 2021 NIH budget request, a yearly opportunity to update lawmakers on his agencys progress and priorities. Thanks to three decades of research that dates in part back to his own NIH-backed work at the University of Michigan, for instance, the US has ushered in its first triple therapy for cystic fibrosis last year.

These are dramatic times for NIH research, the director concluded.

Bolstering the burst in new scientific discovery and therapeutic development has been an impressive growth in NIH funding. President Donald Trump may be proposing to cut its budget down 7% next year, but over the past five years it has increased by $11.6 billion, or 39%, according to Rep Rosa DeLauro, chair of the House Appropriations subcommittee on Labor, Health & Human Services and Education. That has translated to a $8 billion boost to the total amount of grants awarded between 2014 and 2019, per NIH disclosure.

The steady increases you have provided have brought new life to biomedical research and built the foundation for us to take on new and unexpected challenges, Collins said, challenges like the one thats on everyones mind right now: the global coronavirus outbreak.

What does this new life look like on the ground? Endpoints News spoke to researchers, administrators and advocates, who pointed to different metrics that either measure output or the environment that scientists find themselves working in. The conversations suggest while the increases which followed years of stagnation did pump more resources into translatioal research, they didnt quite solve the challenges basic science still faces.

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Tackling inherited blindness, Editas and Allergan use CRISPR for the first time in the human body - Endpoints News

Recommendation and review posted by Bethany Smith

AGN-151587 (EDIT-101) is the firstin vivoCRISPR medicine to be administered to patients

Additional patient enrollment to the BRILLIANCE Clinical Trial is ongoing

DUBLIN, Ireland and CAMBRIDGE, Mass., March 04, 2020 (GLOBE NEWSWIRE) -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, and Editas Medicine, Inc. (Nasdaq: EDIT), a leading genome editing company, today announced the treatment of the first patient in the BRILLIANCE clinical trial of AGN-151587 (EDIT-101) at Oregon Health & Science University (OHSU) Casey Eye Institute, a world-recognized academic eye center.

AGN-151587 (EDIT-101) is an experimental medicine delivered via sub-retinal injection under development for the treatment of Leber congenital amaurosis 10 (LCA10), an inherited form of blindness caused by mutations in the centrosomal protein 290 (CEP290) gene. The BRILLIANCE clinical trial is a Phase 1/2 study to evaluate AGN-151587 for the treatment of patients diagnosed with LCA10 and is the worlds first human study of an in vivo, or inside the body, CRISPR genome editing medicine. The trial will assess the safety, tolerability, and efficacy of AGN-151587 in approximately 18 patients with LCA10.

This dosing is a truly historic event for science, for medicine, and most importantly for people living with this eye disease, said Cynthia Collins, President and CEO, Editas Medicine. The first patient dosed in the BRILLIANCE clinical trial marks a significant milestone toward delivering on the promise and potential of CRISPR medicines to durably treat devastating diseases such as LCA10. We look forward to sharing future updates from this clinical trial and our ocular program.

Currently patients living with LCA10 have no approved treatment options. For years, Allergan has had an unwaveringcommitmentto advancingeyecare treatments. With the first patient treated in this historic clinical trial, we mark a significant step in advancing the AGN-151587 clinical program and move closer to our goal of developing a game-changing medicine for LCA10 patients, said Brent Saunders, Chairman and CEO, Allergan.

Our first treatment in this clinical trial is an important step toward bringing new and promising treatments to patients with disease-causing gene mutations. OHSU is honored to be involved in this effort to address previously untreatable diseases such as Leber congenital amaurosis 10, said Mark Pennesi, M.D., Ph.D., Associate Professor of Ophthalmology, Kenneth C. Swan Endowed Professor, Division Chief, Paul H. Casey Ophthalmic Genetics, Casey Eye Institute, Oregon Health & Science University, Principal Investigator and enrolling physician of the first patient treated with AGN-151587.

Eric A. Pierce, M.D., Ph.D., Director of the Inherited Retinal Disorders Service and Director of the Ocular Genomics Institute at Massachusetts Eye and Ear, and the William F. Chatlos Professor of Ophthalmology at Harvard Medical School, and a Principal Investigator for the BRILLIANCE clinical trial also commented, We have a long history at Massachusetts Eye and Ear of helping develop life-changing medicines for our patients, and we are thrilled to be a leader in the development of a CRISPR-based experimental medicine to treat CEP290-associated retinal disease with Allergan and Editas.

About the BRILLIANCE Phase 1/2 Clinical Trial of AGN-151587 (EDIT-101)The BRILLIANCE Phase 1/2 clinical trial of AGN-151587 (EDIT-101) for the treatment of Leber congenital amaurosis 10 (LCA10) will assess the safety, tolerability, and efficacy of AGN-151587 in approximately 18 patients with this disorder. Up to five cohorts of patients across three dose levels will be enrolled in this open label, multi-center, clinical trial. Both adult and pediatric patients (3 17 years old) with a range of baseline visual acuity assessments are eligible for enrollment. Patients will receive a single administration of AGN-151587 via subretinal injection in one eye. Additional details are available on http://www.clinicaltrials.gov (NCT#03872479).

About AGN-151587 (EDIT-101)AGN-151587 (EDIT-101) is a CRISPR-based experimental medicine under investigation for the treatment of Leber congenital amaurosis 10 (LCA10). AGN-151587 is administered via a subretinal injection to deliver the gene editing machinery directly to photoreceptor cells.

About Leber Congenital AmaurosisLeber congenital amaurosis, or LCA, is a group of inherited retinal degenerative disorders caused by mutations in at least 18 different genes.It is the most common cause of inherited childhood blindness, with an incidence of two to three per 100,000 live births worldwide.Symptoms of LCA appear within the first years of life, resulting in significant vision loss and potentially blindness.The most common form of the disease, LCA10, is a monogenic disorder caused by mutations in the CEP290 gene and is the cause of disease in approximately 2030 percent of all LCA patients.

About the Editas Medicine-Allergan AllianceIn March 2017, Editas Medicine and Allergan Pharmaceuticals International Limited (Allergan) entered a strategic alliance and option agreement under which Allergan received exclusive access and the option to license up to five of Editas Medicines genome editing programs for ocular diseases, including AGN-151587 (EDIT-101).Under the terms of the agreement, Allergan is responsible for development and commercialization of optioned products, subject to Editas Medicines option to co-develop and share equally in the profits and losses of two optioned products in the United States. Editas Medicine is also eligible to receive development and commercial milestones, as well as royalty payments on a per-program basis.The agreement covers a range of first-in-class ocular programs targeting serious, vision-threatening diseases based on Editas Medicines unparalleled CRISPR genome editing platform, including CRISPR/Cas9 and CRISPR/Cpf1 (also known as Cas12a). In August 2018, Allergan exercised its option to develop and commercialize AGN-151587 globally for the treatment of LCA10. Additionally, Editas Medicine exercised its option to co-develop and share equally in the profits and losses from AGN-151587 in the United States.

About Allergan plcAllergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a global pharmaceutical leader focused on developing, manufacturing and commercializing branded pharmaceutical, device, biologic, surgical and regenerative medicine products for patients around the world. Allergan markets a portfolio of leading brands and best-in-class products primarily focused on four key therapeutic areas including medical aesthetics, eye care, central nervous system and gastroenterology. As part of its approach to delivering innovation for better patient care, Allergan has built one of the broadest pharmaceutical and device research and development pipelines in the industry.

With colleagues and commercial operations located in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day.

For more information, visit Allergans website atwww.Allergan.com.

About Editas Medicine As a leading genome editing company,Editas Medicineis focused on translating the power and potential of the CRISPR/Cas9 and CRISPR/Cas12a (also known as Cpf1) genome editing systems into a robust pipeline of treatments for people living with serious diseases around the world.Editas Medicineaims to discover, develop, manufacture, and commercialize transformative, durable, precision genomic medicines for a broad class of diseases. For the latest information and scientific presentations, please visit http://www.editasmedicine.com.

Allergan Forward-Looking StatementsStatements contained in this press release that refer to future events or other non-historical facts are forward-looking statements that reflect Allergans current perspective on existing trends and information as of the date of this release. Actual results may differ materially from Allergans current expectations depending upon a number of factors affecting Allergans business. These factors include, among others, the difficulty of predicting the timing or outcome of FDA approvals or actions, if any; the impact of competitive products and pricing; market acceptance of and continued demand for Allergans products; the impact of uncertainty around timing of generic entry related to key products, including RESTASIS, on our financial results; risks associated with divestitures, acquisitions, mergers and joint ventures; risks related to impairments; uncertainty associated with financial projections, projected cost reductions, projected debt reduction, projected synergies, restructurings, increased costs, and adverse tax consequences; difficulties or delays in manufacturing; and other risks and uncertainties detailed in Allergans periodic public filings with the Securities and Exchange Commission, including but not limited to Allergan's Annual Report on Form 10-K for the year ended December 31, 2019. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

Editas Medicine Forward-Looking StatementsThis press release contains forward-looking statements and information within the meaning of The Private Securities Litigation Reform Act of 1995. The words anticipate, believe, continue, could, estimate, expect, intend, may, plan, potential, predict, project, target, should, would, and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements in this press release include statements regarding the Companies plans with respect to the Phase 1/2 clinical trial for AGN-151587 (EDIT-101).Editas Medicine may not actually achieve the plans, intentions, or expectations disclosed in these forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking statements as a result of various factors, including: uncertainties inherent in the initiation and completion of preclinical studies and clinical trials and clinical development of Editas Medicines product candidates; availability and timing of results from preclinical studies and clinical trials; whether interim results from a clinical trial will be predictive of the final results of the trial or the results of future trials; expectations for regulatory approvals to conduct trials or to market products and availability of funding sufficient for Editas Medicines foreseeable and unforeseeable operating expenses and capital expenditure requirements. These and other risks are described in greater detail under the caption Risk Factors included in Editas Medicines most recent Annual Report on Form 10-K, which is on file with the Securities and Exchange Commission, and in other filings that Editas Medicine may make with the Securities and Exchange Commission in the future. Any forward-looking statements contained in this press release speak only as of the date hereof, and Editas Medicine expressly disclaims any obligation to update any forward-looking statements, whether because of new information, future events or otherwise.

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Allergan and Editas Medicine Announce Dosing of First Patient in Landmark Phase 1/2 Clinical Trial of CRISPR Medicine AGN-151587 (EDIT-101) for the...

Recommendation and review posted by Bethany Smith

THREADNEEDLE ASSET MANAGEMENT LT bought a fresh place in W&T Offshore Inc. (NYSE:WTI). The institutional investor bought 1.9 million shares of the stock in a transaction took place on 12/31/2019. In another most recent transaction, which held on 12/31/2019, HOTCHKIS & WILEY CAPITAL MANAGEM bought approximately 1.5 million shares of W&T Offshore Inc. In a separate transaction which took place on 12/31/2019, the institutional investor, COLUMBIA MANAGEMENT INVESTMENT A bought 1.1 million shares of the companys stock. The total Institutional investors and hedge funds own 63.40% of the companys stock.

In the most recent purchasing and selling session, W&T Offshore Inc. (WTI)s share price decreased by -7.85 percent to ratify at $2.23. A sum of 7588948 shares traded at recent session and its average exchanging volume remained at 2.70M shares. The 52-week price high and low points are important variables to concentrate on when assessing the current and prospective worth of a stock. W&T Offshore Inc. (WTI) shares are taking a pay cut of -68.92% from the high point of 52 weeks and flying high of -5.91% from the low figure of 52 weeks.

W&T Offshore Inc. (WTI) shares reached a high of $2.53 and dropped to a low of $2.20 until finishing in the latest session at $2.48. Traders and investors may also choose to study the ATR or Average True Range when concentrating on technical inventory assessment. Currently at 0.25 is the 14-day ATR for W&T Offshore Inc. (WTI). The highest level of 52-weeks price has $7.18 and $2.37 for 52 weeks lowest level. After the recent changes in the price, the firm captured the enterprise value of $1.05B, with the price to earnings ratio of 1.53. The liquidity ratios which the firm has won as a quick ratio of 0.90, a current ratio of 0.90.

Having a look at past record, were going to look at various forwards or backwards shifting developments regarding WTI. The firms shares fell -21.20 percent in the past five business days and shrunk -45.61 percent in the past thirty business days. In the previous quarter, the stock fell -45.74 percent at some point. The output of the stock decreased -49.32 percent within the six-month closing period, while general annual output lost -55.31 percent. The companys performance is now negative at -59.89% from the beginning of the calendar year.

According to WSJ, W&T Offshore Inc. (WTI) obtained an estimated Overweight proposal from the 3 brokerage firms currently keeping a deep eye on the stock performance as compares to its rivals. 0 equity research analysts rated the shares with a selling strategy, 1 gave a hold approach, 2 gave a purchase tip, 0 gave the firm a overweight advice and 0 put the stock under the underweight category. The average price goal of one year between several banks and credit unions that last year discussed the stock is $7.75.

CRISPR Therapeutics AG (CRSP) shares on Thursdays trading session, jumped 0.28 percent to see the stock exchange hands at $53.41 per unit. Lets a quick look at companys past reported and future predictions of growth using the EPS Growth. EPS growth is a percentage change in standardized earnings per share over the trailing-twelve-month period to the current year-end. The company posted a value of $0.97 as earning-per-share over the last full year, while a chance, will post -$4.97 for the coming year. The current EPS Growth rate for the company during the year is 134.10% and predicted to reach at -10.70% for the coming year. In-depth, if we analyze for the long-term EPS Growth, the out-come was 54.00% for the past five years.

The last trading period has seen CRISPR Therapeutics AG (CRSP) move -27.82% and 59.20% from the stocks 52-week high and 52-week low prices respectively. The daily trading volume for CRISPR Therapeutics AG (NASDAQ:CRSP) over the last session is 1.09 million shares. CRSP has attracted considerable attention from traders and investors, a scenario that has seen its volume jump 1.13% compared to the previous one.

Investors focus on the profitability proportions of the company that how the company performs at profitability side. Return on equity ratio or ROE is a significant indicator for prospective investors as they would like to see just how effectively a business is using their cash to produce net earnings. As a return on equity, CRISPR Therapeutics AG (NASDAQ:CRSP) produces 11.70%. Because it would be easy and highly flexible, ROI measurement is among the most popular investment ratios. Executives could use it to evaluate the levels of performance on acquisitions of capital equipment whereas investors can determine that how the stock investment is better. The ROI entry for CRSPs scenario is at 4.90%. Another main metric of a profitability ratio is the return on assets ratio or ROA that analyses how effectively a business can handle its assets to generate earnings over a duration of time. CRISPR Therapeutics AG (CRSP) generated 9.60% ROA for the trading twelve-month.

Volatility is just a proportion of the anticipated day by day value extendthe range where an informal investor works. Greater instability implies more noteworthy benefit or misfortune. After an ongoing check, CRISPR Therapeutics AG (CRSP) stock is found to be 7.79% volatile for the week, while 6.59% volatility is recorded for the month. The outstanding shares have been calculated 56.28M. Based on a recent bid, its distance from 20 days simple moving average is -1.43%, and its distance from 50 days simple moving average is -6.74% while it has a distance of 5.15% from the 200 days simple moving average.

The Williams Percent Range or Williams %R is a well-known specialized pointer made by Larry Williams to help recognize overbought and oversold circumstances. CRISPR Therapeutics AG (NASDAQ:CRSP)s Williams Percent Range or Williams %R at the time of writing to be seated at 15.77% for 9-Day. It is also calculated for different time spans. Currently for this organization, Williams %R is stood at 48.53% for 14-Day, 54.57% for 20-Day, 72.13% for 50-Day and to be seated 59.61% for 100-Day. Relative Strength Index, or RSI(14), which is a technical analysis gauge, also used to measure momentum on a scale of zero to 100 for overbought and oversold. In the case of CRISPR Therapeutics AG, the RSI reading has hit 47.64 for 14-Day.

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Emerging Stocks to Watch: W&T Offshore Inc. (WTI) and CRISPR Therapeutics AG (CRSP) - BOV News

Recommendation and review posted by Bethany Smith

On Tuesday, shares of CRISPR Therapeutics AG (NASDAQ:CRSP) marked $51.15 per share versus a previous $53.35 closing price. With having a -4.12% loss, an insight into the fundamental values of CRISPR Therapeutics AG, investors would also find a great ally in the technical patterns of the stock movements showed in stock charts. CRSP showed a fall of -16.02% within its YTD performance, with highs and lows between $33.55 $74.00 during the period of 52 weeks, compared to the simple moving average of 0.96% in the period of the last 200 days.

Evercore ISI equity researchers changed the status of CRISPR Therapeutics AG (NASDAQ: CRSP) shares from Outperform to a In-line rating in the report published on February 3rd, 2020. Other analysts, including William Blair, also published their reports on CRSP shares. William Blair repeated the rating from the previous report, marking CRSP under Outperform rating, in the report published on November 19th, 2019. Additionally, CRSP shares got another Outperform rating from Oppenheimer, setting a target price of $65 on the companys shares, according to the report published in November 12th, 2019. On August 1st, 2019, Jefferies Initiated an Buy rating and increased its price target to $64. On the other hand, Canaccord Genuity Initiated the Buy rating for CRSP shares, as published in the report on July 26th, 2019. ROTH Capital seems to be going bullish on the price of CRSP shares, based on the price prediction for CRSP, indicating that the shares will jump to $50, giving the shares Buy rating based on their report from June 10th, 2019. Another Outperform rating came from Evercore ISI.

The present dividend yield for CRSP owners is set at 0, marking the return investors will get regardless of the companys performance in the upcoming period. However, in order for the company to be able to pay its dividends, just like it is the case with CRISPR Therapeutics AG, the company needs to provide a healthy cash flow, currently at the value of 57.57. In addition, the growth of sales from quarter to quarter is recording 66870.40%, hinting the companys progress in the upcoming progress.

In order to gain a clear insight on the performance of CRISPR Therapeutics AG (CRSP) as it may occur in the future, there are more than several well-rounded types of analysis and research techniques, while equity is most certainly one of the more important indicators into the companys growth and performance. In this case, you want to make sure that the return on the present equity of 11.70% is enough for you to make a profit out of your investment. You may also count in the quick ratio of the company, currently set at 17.30 so you would make sure that the company is able to cover the debts it may have, which can be easily seen in annual reports of the company.

Set to affect the volatility of a given stock, the average volume can also be a valuable indicator, while CRSP is currently recording an average of 1.10M in volumes. The volatility of the stock on monthly basis is set at 6.43%, while the weekly volatility levels are marked at 9.16%with 2.53% of gain in the last seven days. Additionally, long-term investors are predicting the target price of $75.96, indicating growth from the present price of $51.15, which can represent yet another valuable research and analysis points that can help you decide whether to invest in CRSP or pass.

CRISPR Therapeutics AG (CRSP) is based in the Switzerland and it represents one of the well-known company operating with Healthcare sector. If you wish to compare CRSP shares with other companies under Electronic Equipment and Consumer Goods, a factor to note is the P/E value of 52.68 for CRISPR Therapeutics AG, while the value can represent an indicator in the future growth of the company in terms of investors expectations. The later value should have a steady growth rate, increasing and growing gradually, which serves the purpose of reliably showcasing the progress of the company. The value 0.97 is supported by the yearly ESP growth of 134.10%.

Besides from looking into the fundamentals, you should also note the number of people inside the company owning the shares, as the values should be in line with the expectations of investors. In that spirit, the present ownership of stocks inside the company is set at 0.30%, which can provide you with an insight of how involved executives are in owning shares of the company. In oppose to the executives share, the institutional ownership counts 53.40% of shares, carrying an equal significance as an indicator of value, as the presence of large investors may signal a strong company.

It appears that more than several institutional investors and hedge funds decided to increase stakes in CRSP in the recent period. That is how Nikko Asset Management Americas, now has an increase position in CRSP by 9.80% in the first quarter, owning 3.05 million shares of CRSP stocks, with the value of $158.42 million after the purchase of an additional 272,139 shares during the last quarter. In the meanwhile, ARK Investment Management LLC also increased their stake in CRSP shares changed 6.27% in the first quarter, which means that the company now owns 2.96 million shares of company, all valued at $153.6 million after the acquisition of additional 174,495 shares during the last quarter.

Federated Global Investment Manag acquired a new position in CRISPR Therapeutics AG during the first quarter, with the value of $65.55 million, and T. Rowe Price Associates, Inc. increased their stake in the companys shares by 59.00% in the first quarter, now owning 411,929 shares valued at $57.67 million after the acquisition of the additional 1.11 million shares during the last quarter. In the end, Credit Suisse Asset Management increased their position by 48.41% during the first quarter, now owning 770792 CRSP shares, now holding the value of $40.04 million in CRSP with the purchase of the additional 760,000 shares during the period of the last quarter. At the present, 53.40% of CRSP shares are in the ownership of institutional investors.

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Here's The Case for and Against CRISPR Therapeutics AG (CRSP) - US Post News

Recommendation and review posted by Bethany Smith

Global CRISPR Technology Market 2020-2025

Holistic research derivatives focusing on Global CRISPR Technology Market is a high-grade professional overview of various market determinants and factors representing factors, challenges, trends, threats, and a holistic overview that determine the overall growth directive of the Global CRISPR Technology Market. This intricate research report on QY Reports also lends considerable focus on other growth prospects compiling a holistic mix of crucial determinants such as product portfolio, application description as well as technological sophistication that have a huge impact on the growth prospective of the Global CRISPR Technology Market.

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Top Players Included In This Report:Thermo Fisher ScientificMerck KGaAGenScriptIntegrated DNA Technologies (IDT)Horizon Discovery GroupAgilent TechnologiesCellectaGeneCopoeiaNew England BiolabsOrigene TechnologiesSynthego CorporationToolgen

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Report readers are presented with thought provoking insights on various core facets inclusive of product portfolio, payment structure, transaction interface as well as technological sophistication that crucially enlighten the growth prognosis of the target market. A thorough analytical review of regional break-up is also included in the trailing sections of the report before proceeding with the competitive landscape overview.

The research report offers a point-to-point thorough description about innumerable market-based information encompassing dominant trends, restraints, drivers, as well opportunities widely prevalent in the market and their subsequent impact on smooth functioning of the target market. Further to this, the Global CRISPR Technology Market report holistically touches upon well-demonstrated data sources and insightful growth influencers about multiple manufacturers and market behemoths working closely in the Global CRISPR Technology Market. This report also encapsulates supply chain facets, economic factors and financial data particulars, comprising a range of products & services varieties, intense developments, as well as elaborate analysis of various acquisitions & mergers scenario, present & other future ready growth opportunities and trends that have a direct impact on Global CRISPR Technology Market as well as advances, inclusive of technological sophistication, that carefully craft market players footfall in the Global CRISPR Technology Market, concludes this detailed research offering.

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Types Covered In This Report:EnzymesKitsgRNALibrariesDesign Tools

Applications Covered In This Report:BiomedicalAgricultural

In addition to the factors mentioned above impacting the Global CRISPR Technology Market, this comprehensive research report gauges for decisive conclusions concerning growth factors and determinants, eventually influencing holistic growth and lucrative business models in Global CRISPR Technology Market. Further in the course of the report this research report on Global CRISPR Technology Market identifies notable industry forerunners and their effective business decisions, aligning with market specific factors such as threats and challenges as well as opportunities that shape growth in Global CRISPR Technology Market.

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Few Points From TOC:1 Scope of the Report2 Executive Summary3 Global CRISPR Technology by Players4 CRISPR Technology by RegionsContinued

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Global CRISPR Technology Market is said to have a potential scope for growth in the years by 2025- Thermo Fisher Scientific, Merck KGaA, GenScript,...

Recommendation and review posted by Bethany Smith

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WERNERSVILLE, PA (WPMT) A Berks County mother is battling with insurance companies to get her son the treatment he needs. Doctors have prescribed the toddler the most expensive drug in the world. Yet, his insurance companies deny coverage.

What is my childs life worth to you, asked Jacqueline Brewer, of Berks County.

Brewer has been in a fight with her almost two-year-old son Johns insurance companies for nine months.

Were not giving up, said Brewer.

John was a happy, healthy baby for the first six months of his life.

He was drinking from a bottle, he was nursing, he was great until he picked up a viral infection, said Brewer. it was just a simple cold.

A cold that took a turn for the worse very quickly, appearing to trigger something even worse in John.

Being in the ICU and being intubated and the doctors coming in and saying were going to do more tests and more tests and more tests and theres still nothing coming up, said Brewer. And then they said theyd like to do a genetic panel.

The genetic panel revealed John has spinal muscular atrophy, also known as SMA. Its a muscle wasting disease caused by a mutated chromosome gene.

It goes on and on and on until he basically cant move, said Brewer. He wouldnt be able to move his tongue. His diaphragm would no longer work. And its terrifying.

Johns been receiving a drug called Spinraza every four months, it helps build the proteins his body needs.

Its a little much, it takes a toll on him, said Brewer. Hes getting a stronger. Now, hes able to hold his head up a little bit.

Spinraza has a price tag of more than $100,000 per injection and is covered by Johns insurance. But, since May of 2019, theres something new on the market.

Now theres Zolgensma. Thats the one we need and that would stop the regression, said Brewer.

Zolgensma is the most expensive drug in the world, with a $2.1 million price tag, but John would only need to receive it once. The one-time treatment is actually less expensive than receiving Spinraza for five years.

It would stop where hes at, said Brewer. He would never get any worse and thats what we need.

Yet, insurance companies Aetna and Ameri-Health have continuously denied coverage of the drug.

Every doctor he comes across is saying its medically necessary for this child to have it but theyre [insurance companies] saying no, said Brewer.

Brewer has continued to receive denials letters from Johns insurance companies all saying the same thing: The request for Zolgensma was denied completely because we are not able to establish medical necessity.

Theyre saying its not medically necessary because hes already being supported, said Brewer. Hes already on a ventilator and the Spinraza injections are enough.

But, Brewer says other children with advanced stages of SMA with other insurance providers have been approved for Zolgensma.

Time is also running out for John to receive Zolgensma. The FDA only approved it for children under two-years-old. John turns to March 24th.

Its terrifying because what if they say no and dont budge and hes gonna turn two and theyre not going to budge, said Brewer. But, Im still going to call everyday, his doctors are still calling everyday, they will do everything they can. Were not going to give up. Even if he turns 2, Im not going to give up.

Brewer says she will continue to fight Johns insurance companies every single day, and if he doesnt receive the drug before he turns two, shell look for clinical trials to somehow get John this drug.

I need to know what this innocent childs life is worth, said Brewer

Please note: This content carries a strict local market embargo. If you share the same market as the contributor of this article, you may not use it on any platform.

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Berks County mother fights insurance companies to cover $2 million gene therapy drug for son - KESQ

Recommendation and review posted by Bethany Smith

Mark Christman resented being thought of as a wimp.

As a kid growing up in Indiana Township, hed always felt more like a tough guy, with the inner tenacity, drive and work ethic of a competitive athlete. Christman loved playing sports, but getting picked last on nearly every team was frustrating.

Around age 14, tasks like running laps and picking up a shovel to clean up after the family horse became unnervingly difficult. Hed lift weights for months and gain little to no muscle. And despite being relatively skinny, he had a small pot belly protruding from one side of his stomach.

In 10th grade, Christman joined the wrestling team at Fox Chapel Area High School. He got bigger but not stronger. He couldnt keep up.

He wondered what could be wrong with him.

Several months later, Christman rode the family horse without a saddle. The horse darted off at full speed, knocking him off while tangling his arm in the reins. He told his doctor about other issues the worsening weakness in his arms and legs, his lopsided belly and winged shoulder blade. The doctor sent him to a neurologist.

At age 16, Christman got a diagnosis he didnt know hed been waiting for.

Christman had been born with facioscapulohumeral disease, or FSHD, a rare form of muscular dystrophy that affects about 1 in 8,000 people. A genetic defect causes the overproduction of a protein that kills muscle cells.

The diseases severity can vary widely, from causing total blindness, hearing loss and leg and arm immobility, to people who show few to no symptoms. It has no known cure.

My parents had a really tough time with it, recalled Christman, now a 59-year-old retired business attorney, Whitehall zoning board member and board member of Trib Total Media. For me, I was almost relieved to know: OK, now I know what this is.

I grew up thinking I was a wimp, and I know Im not.

A disease with no cure yet

Christman didnt let the progressive disease get in the way of cultivating a successful professional and personal life.

After marrying his college sweetheart and passing the bar exam, he embarked on a decades-long career in business law while adapting to overcome challenges along the way, from getting around the office and climbing stairs to opening drawers and filing paperwork.

He appreciated the support of his wife, Renee, an elementary school ESL teacher, along with colleagues and strangers who stopped to help him get on the elevator, reach an item on a shelf or get up from a fall. After he opted for a wheelchair, his father drove him from the South Hills to his law firms office every day from 2002 until his retirement in 2015.

But Christman couldnt help feeling misunderstood.

Hed smile politely but felt irked when even close friends asked him, Hows your MS? in reference to an entirely different, nerve-related disease, multiple sclerosis.

A room full of strangers, a room full of friends

For 41 years, Christman never met anyone else who had the same disease as he did. A 2014 event in Boston changed that. At the FSHD Societys Connect Conference, he recalled feeling overcome with emotions when he encountered hundreds of people with varying levels of the FSHD.

The FSHD Society is a nonprofit advocacy and research grant-making group based in Lexington, Mass.

Christman, whos typically an introvert at large gatherings, still gets teary-eyed remembering it.

It was a room full of strangers, and I felt like they were my friends, he said.

Until that cathartic moment, Christman said hes not sure even he realized how isolated hed felt.

My wife is just the best thing that ever happened to me in my life, and I love her dearly but I still felt alone, he said. Everyones experience of the disease is different. But having someone whos shared some of your experiences is a really special thing.

Christman is on a mission to share that gift of connection and empowerment to others across Western Pennsylvania and neighboring states. Last year, he formed Western Pennsylvanias first chapter of the rapidly burgeoning FSHD Society. The organization hopes to accelerate getting promising treatments that could halt the diseases progression to market in as soon as five years.

Christman is searching for more participants and their loved ones to join the group, with at least four dozen believed to be living in the Pittsburgh area.

I want to maybe help other people have that same experience that I had meeting people, said Christman, but also do something to raise money and push this along to find a treatment and a cure.

Christman held the chapters first meeting in June at the National Aviary in Pittsburghs North Side. Seven people attended, including two people with FSHD and their spouses. He expected everyone to want to know the latest research and tips for practical things to make life easier, like how to get an insurance company to approve a more sophisticated, joystick-controlled scooter like his.

Instead, a former coal miner told the group how hard it was for him when he was diagnosed, and a former Aviary employee lamented that her condition forced her to stop working.

All anyone wanted was to talk, Christman said. It was all about sharing.

If you really loved her, you wouldnt marry her

Christman sees the group as a chance for people to discuss things that those who dont know of the disease cant relate to, including its emotional and psychological toll.

Like how his wifes parents reacted when he proposed.

They went on a campaign to stop her, Christman said. They were worried that I wasnt going to be able to support her, and that she was going to have a terrible life. They got me aside and said if I really loved her, I wouldnt marry her.

The week of the wedding, Renees parents called and asked to attend, and did.

They never said anything again, and theyve since apologized, said Christman, adding hes gotten along well with his in-laws ever since. They know they were wrong.

At a recent FSHD event, Christman met a man who feared his children would think less of him for having the disease. Christmans now-adult son reassured the man that wouldnt be the case, that to his kids hed just be dad.

Christman said he may not have been able to play catch, but he made plenty of time to be actively involved in the lives of his three children and never felt like he let them down because of his condition. One of his daughters is a registered nurse, the second is a Hasbro engineer. His son is a teacher.

Theres a 50/50 chance of passing on the gene to a child. But some people have the disease and show few or no symptoms. Christman hasnt identified anyone in his family known to have it.

As a lawyer, Christman sometimes wondered whether his visible physical handicap impacted his clients perception of his mental capabilities.

He wasnt sure whether colleagues thought of him as overly grumpy because of partial facial muscle loss that gives him a half-frown resting face and slightly crooked smile. Hes grateful he hasnt lost his ability to smile, like many people with FSHD do.

Finding patients, expediting treatments

Once the disease gets too far along, the muscles disappear, and theyre replaced by, essentially, scar tissue, said Dr. Paula Clemens, Christmans UPMC neurologist. Once that happens, theres not really a lot of hope in treatments, unless you were to come up with a treatment that would make new muscle, such as by using stem cells an idea thats still a long way from materializing.

The FSHD Society is hoping to expedite the approval of a pill that could stop the disease from getting worse. Formed in 1991 by two patients who have FSH muscular dystrophy, the FSHD Society has focused primarily on raising money for research.

In 2014, newly hired CEO Mark Stone decided that to help expedite the development and approval of newly emerging treatment options, they needed to form local chapters in as many places as possible and get more patients involved and aware of clinical trials.

An estimated 40,000 Americans live with FSHD. But the society is only aware of about 3,500 of them. People may be living with it and not have a formal diagnosis, either because they havent sought one or their doctors havent recognized it.

This is a disease where youve got to also have a very active community, branch coordinator Beth Johnston said, so that if treatments do come to light, they do get to people and you have a disease community who can support it.

The society now has 48 local chapters in 24 states. Its goal is to raise $5 million toward treatment efforts this year.

In addition to providing education and support groups, the society is working directly with medical researchers and officials at the Food and Drug Administration to lobby for expediting clinical trials that appear promising.

Theyre helping us to understand how to accelerate the process that they have in order to get the drugs on the market, Johnston said. Weve got to activate our community. This is such a critical time in therapy development, its super important.

You just adapt

Christman continues to struggle with some tasks on a daily basis, but he has managed to work around his limitations.

You just adapt, he said.

These days, his wife helps him shower and get dressed.

His dad, 85, still drives him to Giant Eagle.

He loves using his iPad and other devices that are operated via voice control, since he has trouble punching keyboards or touch screens with more than one finger. He has a hard time lifting his hands, so hell lean in to do so instead. He can move his right leg to the side, but cant extend it forward.

Alexa, tell Delta to pour one cup water, hell say to the Amazon device beside the kitchen sink that controls the hard-to-reach faucet.

Hes thankful for the work of Carnegie Mellon University students who helped to build him a special tool to use the oven.

A few months ago, Christman and his wife completed a full kitchen renovation that includes an oven with a door that opens sideways as opposed to outward, plenty of reachable cupboard space and a special pull-out feature for him to use his Kitchen Aid mixer.

He has a passion for cooking, especially baking bread. His Whitehall homes bookshelves are stocked with titles like The Bread Bakers Guide, Baking with Julia, Bernard Claytons New Complete Book of Breads and, for meals with an extra kick, The Sriracha Cookbook.

I love it when he cooks dinner with me, said Renee Christman, recalling a recent meal featuring her husbands homemade pizza crust.

In addition to his municipal and board roles, Christman enjoys taking courses through the Osher Lifelong Learning Institute at CMU. Some of his favorites so far include the masters of architecture, the role of food in history, psychology of decision-making and a course on cybercurrency. Hes participating in a CMU pilot project to build more accessible video games.

Even though its getting tougher, hes determined to do tasks like putting on his own coat for as long as he can.

My theory is, if I just let someone else do it all the time, Im not going to be able to do it anymore, Christman said.

But Christman said hes also getting better at accepting help when he needs it. He regrets delaying getting a wheelchair for years, only to realize how much more freedom it gave him.

I want to empower patients, because a lot of people dont know a lot about their disease and whats happening to them, he said. They want to learn and be with people who have gone through similar things. They want to tell their story.

The next meeting of the FSHD Societys Western Pennsylvania chapter is scheduled for 1 to 3 p.m. April 5 at the Carnegie Library branch in Pittsburghs Squirrel Hill neighborhood. For more information, go to FSHDSociety.org, email WesternPAChapter@fshdsociety.org or visit the group on Facebook.

Natasha Lindstrom is a Tribune-Review staff writer. You can contact Natasha at 412-380-8514, nlindstrom@tribweb.com or via Twitter .

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Retired attorney with rare muscular disease FHSD connects with others and accelerates search for cure - TribLIVE

Recommendation and review posted by Bethany Smith

SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)--Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to Esbriet (pirfenidone) for adults with unclassifiable interstitial lung disease (uILD). The designation was granted based on data from a Phase II trial, which studied the efficacy and safety of Esbriet in uILD. The study represented the first randomized controlled trial to exclusively enroll patients with progressive fibrosing uILD.

Todays milestone for Esbriet builds on our continued commitment to improving the standard of care for people living with fibrotic lung diseases, said Levi Garraway, M.D., Ph.D., chief medical officer and head of Global Product Development. We look forward to discussing the data with the FDA with the hope of bringing our important medicine to those with uILD who are currently without a treatment option.

ILD is a term that broadly describes a diverse group of more than 200 types of rare pulmonary diseases. While ILDs share similar features, including cough and shortness of breath, each ILD has different causes, treatment approaches, and outlooks. Approximately 10% of people living with ILD reviewed by a multidisciplinary team cannot be given a definitive diagnosis, even after a thorough investigation, and in these cases, people are categorized as having uILD.

The Phase II data supporting Breakthrough Therapy Designation were recently presented as a late-breaking abstract at the 2019 European Respiratory Societys annual meeting and simultaneously published in The Lancet Respiratory Medicine. The data suggested Esbriet slowed disease progression and supported its efficacy on a number of lung function parameters including forced vital capacity (FVC), in people with uILD. The safety and tolerability profile of Esbriet in people with uILD was comparable with that observed in Phase III trials in people with idiopathic pulmonary fibrosis (IPF).

Breakthrough Therapy Designation is designed to accelerate the development and review of medicines intended to treat serious or life-threatening conditions with preliminary evidence that indicates they may demonstrate a substantial improvement over existing therapies. This is the 33rd Breakthrough Therapy Designation for Genentechs portfolio of medicines.

About the Phase II Study

This international, multicenter, double-blind, randomized, placebo-controlled Phase II trial at 70 centers included patients (aged 18-85 years) with progressive fibrosing uILD, a percent predicted forced vital capacity (FVC) of 45% or higher and percent predicted carbon monoxide diffusing capacity (DLco) of 30% or higher, more than 10% fibrosis on high-resolution CT, and a high-resolution CT from the previous 12 months.

The primary endpoint was mean predicted change in FVC from baseline over 24 weeks, measured by daily home spirometry. Secondary endpoints were change in FVC measured by site spirometry, proportion of patients who had a more than 5% or more than 10% absolute or relative decline in percent predicted FVC measured by clinic-based spirometry, change in percent predicted DLco, change in 6-min walk distance (6MWD), change in University of California San Diego-Shortness of Breath Questionnaire (UCSD-SOBQ) score, change in Leicester Cough Questionnaire score, change in cough visual analogue scale, and changes in total and subscores of the St. George's Respiratory Questionnaire (SGRQ), all of which were compared with baseline.

Analysis of the primary endpoint was affected by intraindividual variability in home spirometry values, which prevented application of the prespecified statistical model to the primary endpoint assessment. Over 24 weeks, predicted median change in FVC measured by home spirometry was -87.7 mL (Q1-Q3 -338.1 to 148.6) in the pirfenidone group versus -157.1 mL (370.9 to 70.1) in the placebo group. Over 24 weeks, predicted mean change in FVC measured by site spirometry was lower in patients given pirfenidone than placebo (treatment difference 95.3 mL, p=0.002). Results for DLco and 6MWD generally trended in favor of pirfenidone treatment. Adverse event reporting reflected the known safety profile of pirfenidone. The most common treatment-related treatment-emergent adverse events were gastrointestinal disorders (47% in the pirfenidone group vs 26% in the placebo group), fatigue (13% vs 10%), and rash (10% vs 7%). Pirfenidone treatment was associated with less loss to lung function and exercise capacity compared with placebo over 24 weeks. The results of this study suggest that patients with progressive fibrosing uILD may benefit from pirfenidone therapy.

About Esbriet

Esbriet is an oral medicine approved for the treatment of IPF and is available in more than 60 countries worldwide. Esbriet was approved for use in Europe in 2011 in adults with mild-to-moderate IPF and in the U.S. in people with IPF in October 2014. In early 2017, the U.S. Food and Drug Administration (FDA) approved the Esbriet 801 mg and 267 mg tablets as new options for administering the medicine for the treatment of IPF. The 801 mg tablets, which are now available in the U.S., offer people with IPF a maintenance option for taking Esbriet with fewer pills per day.

What is Esbriet?

Esbriet is a prescription medicine used to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF).

It is not known if Esbriet is safe and effective in children.

Select Important Safety Information

Before you take Esbriet, tell your doctor if you:

What are the possible side effects of Esbriet?

Esbriet may cause serious side effects, including:

A healthcare provider may change the dose or discontinue Esbriet if side effects do not go away.

The most common side effects of Esbriet include upper respiratory tract infections, feeling tired, headache, dizziness, loss of appetite, sinusitis, insomnia, or weight loss.

These are not all the possible side effects of Esbriet.

What should patients avoid while taking Esbriet?

Patients should call their doctor for medical advice about side effects. Patients may report side effects to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch or to Genentech at 1-888-835-2555.

Please see full Prescribing Information, including Patient Information, for additional important safety information at http://www.esbriet.com.

About Genentech

Founded more than 40 years ago, Genentech is a leading biotechnology company that discovers, develops, manufactures and commercializes medicines to treat patients with serious and life-threatening medical conditions. The company, a member of the Roche Group, has headquarters in South San Francisco, California. For additional information about the company, please visit http://www.gene.com.

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FDA Grants Breakthrough Therapy Designation for Genentech's Esbriet (pirfenidone) in Unclassifiable Interstitial Lung Disease - Business Wire

Recommendation and review posted by Bethany Smith

Cryonics is the practice of preserving human bodies in extremely cold temperatures with the hope of reviving them sometime in the future. The idea is that, if someone has "died" from a disease that is incurable today, he or she can be "frozen" and then revived in the future when a cure has been discovered. A person preserved this way is said to be in cryonic suspension.

To understand the technology behind cryonics, think about the news stories you've heard of people who have fallen into an icy lake and have been submerged for up to an hour in the frigid water before being rescued. The ones who survived did so because the icy water put their body into a sort of suspended animation, slowing down their metabolism and brain function to the point where they needed almost no oxygen.

Cryonics is a bit different from being resuscitated after falling into an icy lake, though. First of all, it's illegal to perform cryonic suspension on someone who is still alive. People who undergo this procedure must first be pronounced legally dead -- that is, their heart must have stopped beating. But if they're dead, how can they ever be revived? According to scientists who perform cryonics, "legally dead" is not the same as "totally dead." Total death, they say, is the point at which all brain function ceases. Legal death occurs when the heart has stopped beating, but some cellular brain function remains. Cryonics preserves the little cell function that remains so that, theoretically, the person can be resuscitated in the future.

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What Is Cryonics? - How Cryonics Works | HowStuffWorks

Recommendation and review posted by Bethany Smith

As pet deathcare providers, we assist families with the euthanasia process in their own homes and with the disposition of their pets body once death has occurred. Most families chose traditional dispositions like burial or cremation. Less frequently, they may choose something untraditional, like taxidermy. This would be the first time weve ever worked with clients who requested cryogenic preservation.

It was nearly 7:30 pm in Richmond, California, in late March of 2018, and from the crest where I stood I could see the last dregs of the sun slipping below the horizon. Across the Bay, the silhouette of San Francisco was drenched in shades of hazy sherbet. My husband Derek and I held hands as we slipped inside the corner houses gate and knocked on the door. His black medical kit, a plain bag, was slung over one shoulder to hang on his hip.

Laura, a tall, online psychology professor in her fifties with a background in hospice and crisis line work, ushered us inside. Her son, Jordan, a quiet 27-year-old college student, slipped into the room after us. We were there to meet Dakota, a 14-year-old mixed breed dog who was dying of right-sided heart failure.

In late April 2017, our own dog Harper was dying of heart failure, too. We eventually euthanized her in our living room, sitting on our red leather couch, with our favorite band playing quietly from the speakers as I held her to my chest the same way we took naps together over our nine years together. Once she died, I placed her in a casket lined with a bright pink towel and surrounded her body with flowers and her favorite treats. We took pictures of her before the procedure and after she was arranged in her casket. Then we drove to the crematory. I placed her body in the retort myself, and we picked her up an hour later. Sitting in our parked car with her urn in my lap, we decided to open a veterinary practice focused on providing in-home hospice, palliative care, and euthanasia. Derek was a veterinarian; I worked as a licensed funeral director, embalmer, and crematory operator across the Bay Area before moving to pet deathcare. We believed that a good death was an integral part of a good life.

Hospice and palliative care is healthcare focused on maximizing quality of life, usually for terminally ill patients. Dakota the dog was that kind of patient. He had right-sided heart failure, a chronic condition in which the heart muscle or valves doesnt pump blood efficiently. As a result, the fluids back up into the abdomen. (Left-sided heart failure causes the blood to back up in the lungs instead, leading to breathing problems and eventual suffocation.) Laura and Jordan had been managing Dakotas illness with medication, administration of concentrated oxygen, and periodic drainage of the fluid from his abdomen. Ultimately, most causes of heart disease in dogs are not reversible conditions. Death is not a matter of if, but when.

Normally, we advise that families choose euthanasia over a natural death. As we explain it, the body is a machine whose dominant goal is to continue functioning. It will push to do so regardless of pain or difficulty. Euthanasia hastens the natural dying process as painlessly as we know how to with current medical science. Jordan and Laura wanted Dakota to die naturally, without the assistance of euthanasia medications, but they also wanted to ensure his pain was managed.

As a veterinarian, my primary role and ethical imperative is to advocate on behalf of the pet, who is at a disadvantage in the decision-making process to begin with, Derek explains, as he remembers Dakota. Even at the expense of disappointing or angering the owner, advocating for the most ethical death experience is forefront. If Dakota had been dying of left-sided heart failure, the type that causes suffocation, Derek would have insisted on euthanasia as the most humane and ethical choice. Because Dakota was experiencing right-sided heart failure instead, a natural death was acceptable because the amount of suffering was minimal. (Pain is one type of suffering, but there are many different types of suffering, including nausea, malaise, fatigue, and fear.) Derek and I provided a hospice Emergency Comfort Kit filled with sedatives and pain relief, as encouraged by the International Association for Animal Hospice and Palliative Care.

Jordan let us know that they were interested in cryogenically preserving Dakotas body after death, a process he first learned about when he was a teenager. My dad died when I was 10, Jordan would later tell me. I think that sort of really made me more aware of mortality in a way most 10-year-olds arent. He and Laura arranged to have Dakota received at the Cryonics Institute (CI) in Detroit, Michigan, a place that describes cryonics as a form of one-way medical time travel. Cryopreservation is the process where biological tissue, like a body, is cooled to very low temperatures with the intention of stopping chemical processes that might cause damage to the tissue, like decomposition. The bodies (or patients, as theyre referred to in the industry) are held in a dewar, a tall stainless steel vat. Ultimately, the end goal of cryopreservation is to hold the body in stasis until new technology is invented that can reverse or cure the injury or ailment that caused death.

Cryopreservation of tissue isnt a new concept. In 1964, a physics teacher named Robert Ettinger published The Prospect of Immortality, a book which promoted the concept of cryonics. By 1972, the first cryonics organization was founded (a company now called Alcor, located in Scottsdale, AZ.) And the technology used in the cryopreservation process is even older than that.

The tech we use goes back to the time of Queen Victoria, Steve Garan tells me over the phone. Garan is the Chief Technology Officer of TransTime, a cryonic suspension service out of San Leandro, CA that was founded in 1974. Hes also a Research Fellow at UC Berkeley, the Director of Bioinformatics at the Center for Research & Education on Aging, and a researcher at the Lawrence Berkeley National Laboratory. Cryogenic liquids were synthesized back in the late 1800s... The dewar was developed back in the 1800s as well. We use Victorian technology.

Cryopreservation of biological material has included semen, blood, tissues like tumors, eggs, embryos, ovarian tissue, and plant seeds, but as of yet no human has been cryopreserved and revived. In order to do that, youd have to cure whatever caused their death, chuckles Garan. ...[But] there are people walking around today that were frozen embryos, he offers as proof of concept. For every open letter on cryonic justification signed by scientists, you can find a similar counterargument denouncing it as snake oil mixed with false hopes.

In Richmond, Derek and I gently counseled Laura and Jordan about the scientific validity of cryonics, ensuring they fully understood that there is, as of yet, no proof as to the likelihood of success. The contract they signed with CI is similarly shrouded in dire legal jargon: Laura and Jordan must represent that they understand cryonic cryopreservation is an unknown, untested process, and that no human being, or any adult vertebrate, has ever been successfully cryonically suspended and revived, and that the success of cryopreservation depends on future advances in science and technology and that the probability of success is completely unknown. CI charged $7,300 for the privilege of storing Dakotas body after death, excluding the costs of shipping his body there as soon as possible after dying.

Laura doesnt disagree. I would not advise anybody to do it, she tells me frankly, speaking quickly but clearly. I think theyre just throwing money away. She used life insurance money from her husbands death to cover most of the costs and bridged the gap by borrowing from her retirement fund. Jordan still feels gratitude about both the money spent and the fact that spending it didnt affect their quality of life. He plans to repay her once hes graduated and making money.

Derek and I agree that besides the necessity of ensuring the comfort of the pet, a huge part of our work is focused on helping the family find comfort in their moment of grief. If money is a tool meant to improve our lifes experience while were living, and cryopreservation of Dakotas body contributes to a sense of solace for Laura and Jordan, then we have successfully completed at least one facet of our job.

Laura acknowledges that shes choosing of her own free will and volition to sign the paperwork, pay the fees, and send Dakota (and, eventually, in February 2020, their 16-year-old dog Maggie, too) to be cryopreserved. But she believes the industry preys upon peoples fear of death.

It magnifies my fear of death, she explains. It makes me more afraid to die. Im concerned they might start cryopreserving me before Im fully dead, I might feel it, it might be painful. And the thought of waking up a millennium from now, surrounded by people with different customs, technology, and languages, contributes to her fear.

She wont fully commit to saying that patients will never be revivedshes been wrong beforebut posits that the number of variables that have to fall into place for it to happen seem unlikely. There are so many factors that are going to have to work out perfectly.

Jordan himself isnt actually fully sold on the feasibility, either. I think theres a reasonable enough chance that its worth doing, he explains carefully, his measured cadence in direct opposition to his moms rapid-fire responses. I sort of see it like an insurance policy. I mean, if youre decomposed in the ground or burnt to ash [via cremation], theres basically a zero percent chance of ever living again. He likens it to Pascals Wager, a philosophical argument that posits humans bet with their lives in the existence or nonexistence of God. Pascals Wager argues that a rational person should live as though God exists, as his nonexistence will result in finite loss, whereas they stand to receive infinite gains (an eternity in Heaven) or suffer infinite loss (eternity in hell) for atheism.

Jordans other big argument is the shifting litmus test for what constitutes death. Through most of the existence of animal life, if your heart stops, youre dead, he says. But now, of course, theres plenty of people who have gone into cardiac arrest and been resuscitated. Look at someone like Dick Cheney, who was alive without a heartbeat walking and talking. (After a series of heart attacks, Cheney had a small pump called a left ventricular assist device installed while waiting for a heart transplant. The devices creates continuous blood flow and results in no pulse or measurable blood pressure.)

After Derek and I left, we exchanged emails with Laura late into the evening, collecting information about the requirements to ship Dakotas body to CI. We originally planned to use UPS. Per CIs instructions, Dakota should be wrapped in a towel, contained within a plastic bag, tucked into a good quality cooler secured with clear tape, cooled with bags of ice. From there, he should be packed into a large cardboard box and shipped as an animal diagnostic specimen. The words dead dog or dead animal were not to be used, lest they cause the UPS employee to refuse the package. Time, we were told, is of the essence. With cryopreservation of people, if there is advance warning of the death, the patient is placed in an ice bath within seconds of clinical death being declared. Decomposition begins immediately.

Dakota died overnight. The dogs death led to a mad scramble, where the best laid plans of veterinarians and cryonic institutes ultimately go awry when two UPS employees refuse the shipment. I did what I could to assist with the process, but my hands were tied by the failure of the UPS to follow their own bureaucratic policies. My contact at CI told me this kind of screw-up is a rarity and depends solely on the employee; they claimed to have received another pet via UPS shipment through without issue.

One full day passes. Then another. Derek and I worried and wondered about what happened. Did Dakota get there? Even if Dakota got there, would he be able to be cryopreserved? Does water ice even follow the appropriate standards for good cryopreservation? Were we helping our clients get ripped off by assisting in this process?

I eventually found out that Laura was put in touch with Garan at TransTime, who delivered Dakotas body in person via commercial flight from California to Michigan. TransTime doesnt normally handle the cryopreservation of pets, but Garan is also a pet owner; he has a 15-year-old dog named Skippy and could empathize with Lauras predicament. Dogs are like family, he says. We treat them almost like children, in a way. He had no problem assisting with the transfer and he jokes that the x-ray technician who took Dakotas body through security nearly fainted.

Dakota was finally received at CI and his body cryopreserved in a dewar, per Laura and Jordans instructions. Jordan says he was sent a picture of Dakota cryopreserved in Michigan, and tells me he has no worries about it being an outright scam. It seems like it would be a pretty big conspiracy if theyre not really even freezing the bodies, he says.

Even without physically seeing the procedure performed, Lauras gut feeling is also that Dakota was properly preserved and stored. They genuinely believe in what theyre doing. I dont believe theyre consciously setting out to take advantage of people.

For their part, CI Headquarters say they try to be as open as possible so people can find comfort and closure. They have pets shipped via water ice because dry ice freezes a pets smaller body and prevents perfusion, a process involving an injection of cryoprotective solutions that decreases freezing damage to the cells. (Though pets like birds are not perfused because their vascular systems are too small to work with, which means theyre frozen and more likely to suffer damage than a perfused pet.) CI currently has 184 pets in cryopreserved storage.

Garan notes that while the repair job for Dakota may be more difficult because of the time between death and cryopreservation, its not impossible. By the time we get to that point, it may be kind of irrelevant, he says. The technology to do so could exist in the form of bioprinters, biogenerators, nanorobotics, the human/brain cloud... At the end of the day, theres just as much uncertainty about the preservation of a pet as there is about people. The bottom line is they have all the time for technology to do its thing.

When I speak to Laura nearly two years after Dakotas death, shes a week out from her second dogs death. She and Jordan have also elected to have Maggies body cryopreserved, though this time closer to home at TransTime. (Garan, for his part, makes it clear that TransTime will only consider pet cryopreservation if their accompanying human has plans to be preserved as well.)

Both Laura and Jordan felt like cryopreserving Dakota and Maggie was stressful to undergo. I wouldnt call it a pleasant process by any means, says Jordan, though he does point out that working closer to home certainly made things easier. For Laura, the grief of Maggies death combined with the stress of logistics plus the added remorse of money spent has her feeling sad and depressed.

Its almost like with both dogs, I didnt really have a chance to grieve and mourn because there was so much hassle to make this happen. She vacillates between worrying about whether its unhealthy that Jordan has a lifetime of false hope that he might get his dogs back and feeling adamant that its worth it to grant Jordan that modicum of hope and protect him from his fear.

For Jordan, his intense fear of death, of nonexistence, and of a negative afterlife are enough to overpower any frustrations caused through the process. If I did it for myself, but I didnt do it for Maggie and Dakota when I woke up then I would regret it forever, he says.

Ace Ratcliff lives and works in sunny Boynton Beach, FL with their veterinarian husband and a pack of wild beasts. Their hypermobile Ehlers-Danlos Syndrome makes for a rebellious meatcage. They like reading, getting tattooed, and tweeting @mortuaryreport.

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Cryonics, Dakota the Dog, and the Hope of Forever - Gizmodo

Recommendation and review posted by Bethany Smith

(CNN) -

There are only two northern white rhinos left on the planet, and they're both female. Unless scientists can make a dramatic breakthrough, the entire species will die with those two individuals.

In a nondescript building just north of San Diego, California, the fight to save the northern white rhino is coming down to the wire. However, the battleground here looks less like a scene from a wildlife documentary and more akin to something out of a science fiction novel.

At the San Diego Zoo Institute for Conservation Research, an army of scientists armed with liquid nitrogen, microscopes, and ultrasound machines is working around the clock to create an unprecedented first in the conservation world: they are looking to turn frozen rhino skin cells into baby rhinos.

It's not just the science that is groundbreaking, but also the team looking to save this species. Composed mostly of women, the lab is a rarity in a field traditionally dominated by men.

Find out more about Call to Earth and the extraordinary people working for a more sustainable future

The first step in this conservation effort began more than four and a half decades ago in 1975 when scientists established the institute's "Frozen Zoo." In a small room measuring no more than 36 square meters the skin cells of more than 10,000 individuals across 1,100 species sit in giant steel tanks suspended in time, frozen in liquid nitrogen.

Among the collection are the skin samples of 12 northern white rhinos. These are vital to the group's efforts because there is such a small gene pool of living northern whites.

The population has been decimated by poachers, who target rhinos because of the belief in parts of Asia that their horns can cure various ailments. The two surviving females both live under guard at the Ol Pejeta Conservancy in Kenya. Even thoughembryos have been producedin an Italian lab using eggs extracted from the pair, any future descendants from this kind of embryo would carry the genes of those two females.

That may not be enough genetic diversity to maintain a stable population. The hope is that the skin samples of those 12 individuals at the Frozen Zoo contain enough diversity to sustain the northern white species long-term.

The arduous task for these scientists is to create a rhino population from those samples.

Marlys Houck is curator of the Frozen Zoo. She graduated high school in 1979, the same year the Frozen Zoo froze its very first northern white rhino skin cell. She later joined the institute to work on the rhino project.

"I was hired specifically to try to make the cells of the rhinos grow better because they were one of the most difficult to grow cell lines," she told CNN.

Since then, she's figured out how to successfully grow and freeze the skin cells of the northern white.

The impact of this work is not lost on her. "We're losing species so rapidly," she said. "One of the things we can do is save the living cells of these animals before it's too late."

"We're at the forefront of science today," she added. "If we do everything right ... these cells should be here 50 years from now being used for purposes that we can't even imagine today."

Marisa Korody is one of the four scientists tasked with turning these frozen cells into new life. They have to reprogram the frozen skin cells into pluripotent stem cells. In layman's terms, Korody explains that "stem cells can become any cell type in the body if they're given the right signals."

Read: Former war zones turn into wildlife 'paradise'

The aim is to ultimately turn the stem cells into sperm and eggs. The ambitious feat has only been achieved in animals by Japanese scientists. While Korody and her team have looked to that research as a road map, she admits that doing the same with rhinos is uncharted territory. "We don't really know what twists and turns we need to take in order to get from A to B," she said.

"They haven't even figured out how to do this in humans," she added. "We have as much information as we possibly can about humans. We have a fraction of that for rhinos."

Korody says being at the forefront of this kind of science has been a dream job. "This was really the first project that's trying to apply this type of science to conservation as a whole," she said.

She may spend most of her time at work looking through the lens of a microscope, but her mind is always on the final goal for the rhinos: "We want to be able to put them back into the wild one day and have them living free."

Because the remaining two female northern white rhinos can't carry a pregnancy, even if the team can create embryos, the last obstacle is finding rhinos who can carry them to term.

The woman tasked with that job is Barbara Durrant. As the director of reproductive sciences, she's spent four years studying the reproductive systems of six female southern white rhinos at the institute's sister facility, the Nikita Kahn Rhino Rescue Center.

Though the rhinos at the center are a different species, Durrant says they are the closest relative to the northern white. The aim is to eventually have them be surrogates for northern white embryos.

On any given day, Durrant can be found conducting ultrasounds to help her understand each rhino's distinct reproductive cycle. In 2019, two of the center's females gave birth to southern white babies. Both were conceived via artificial insemination, giving Durrant and the teams working on the rhino project hope for the future.

Durrant believes one reason the project works so well is because there are so many women involved. "Women are naturally collaborative with each other," she said. "Because we have so many obstacles along the way and challenges and setbacks, we support each other and we have sympathy for each other."

Read: Rare bird brought back from extinction in the wild

Houck says women tend to be naturally nurturing. "The cells are living little organisms that we're growing and tending almost every day, and I think women are drawn to taking care of something and growing it into something more."

"It's wonderful leading a team of women, and I really think they're changing the world," she added. "People are going to look back and see it was this amazing group of women who quietly, unrecognized, work at this and just get better and better."

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Meet the women racing to save the northern white rhino from extinction - KAKE

Recommendation and review posted by Bethany Smith

I consider my nighttime skincare routine as me time. I always double cleanse; first with Bioderma Sensibio H20 Micellar Water, 10.80, and then I use Rodial Pink Diamond Cleansing Balm, 55, and massage it into my skin. Its a really light and gentle balm that has enough slip for me to be able to easily move it around my face, and it helps dissolve any left over SPF and make-up while also getting rid of the days dirt and grime.

After a good 10-15 minute cleanse, I sweep Pestle and Mortar NMF Lactic Acid Toner, 28, around my face. Lactic acid works underneath the skin, helping to get rid of dead skin cells without dehydrating my skin. Then I press SkinCeuticals HA Intensifer, 90, into my skin to help increase hydration levels.

I use my final product once Im in bed; Decleors Bigarade Neroli Night Balm, 45, which I do a deep pressure massage with and then I finish off using a gua sha to help drain any fluids and relax the muscles.

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3 skin experts share their morning and evening skincare routines - Stylist Magazine

Recommendation and review posted by Bethany Smith

EVERY 20 minutes, someone in the UK is diagnosed with a form of blood cancer, such as leukaemia or lymphoma. It's the fifth most common cancer, and the third biggest cause of cancer deaths.

Yet warning signs of blood cancers can be so unlike those of other cancers, that it's often diagnosed at a very late stage. Research by the blood cancer charity Bloodwise (bloodwise.org.uk) found more than a third of people with blood cancer had to visit their GP three or more times with symptoms before being referred to hospital. This makes it the worst performing cancer in terms of early diagnosis, the charity says.

Why is it so difficult to spot? Well, blood cancers, which stop blood stem cells from working normally and can make you weak and prone to infections, have three main types with many different variations. These variations have numerous diverse symptoms, which can often be mistaken for other less serious conditions.

"Not all signs of blood cancer are easily identifiable, or are associated with typical symptoms of cancer, such as a lump or abnormal mole," explains haematologist Dr Manos Nikolousis, a medical consultant with the blood cancer charity DKMS (dkms.org.uk).

"Blood cancer often presents in ways which are most commonly associated with unrelated and less serious illnesses, like a cold or flu. In other circumstances, patients notice a change in their body which they can't quite put their finger on."

One of the treatments for blood cancer is a stem cell transplant that restores blood-forming stem cells in patients who've had theirs destroyed by very high doses of chemotherapy and/or radiotherapy. But Nikolousis points out that only one in three blood cancer patients who need a transplant will find a matching blood stem cell donor in their family. The remaining two-thirds have to rely on an unrelated donor, which significantly reduces their chance of finding a crucial match.

"The more people who register as potential blood stem cell donors, the better the chances of finding a donor for someone in need," stresses Nikolousis, who points out that potential donors, who should be healthy and aged between 17-55, just need to sign up with DKMS online.

The charity will send a screening kit to obtain a swab from inside the donor's cheeks. If they then prove to be a match for someone, 90 per cent of donations are done by collecting blood and harvesting stem cells from it. The process is simple and could potentially save lives.

What else do you need to know about blood cancer? Here, Nikolousis outlines some blood cancer symptoms and warning signs...

1. Back pain

Musculoskeletal pain in muscles, joints, tendons, bones or structures that support the limbs, neck or back.

2. Bruising or bleeding

One of the most common symptoms associated with blood cancer is bruising, and/or bleeding. The frequency and lasting impact of bruising can be a key warning sign of blood cancer, so it's important to book an appointment with your GP if this develops.

3. Fatigue

Unexplained and persistent tiredness is one of the biggest telltale signs of blood cancer. People who have cancer-related fatigue find it incredibly challenging to complete simple tasks that we tend to take for granted.

4. Swollen lymph nodes/glands

The lymph nodes are small lumps of tissue that contain white blood cells. When inflamed, they can be felt as lumps under the skin; most commonly in the neck, armpit or groin area.

5. Headaches

There may be new headaches that feel different to headaches previously experienced. They're likely to occur frequently and be severe and long-lasting. They also often appear alongside other physical symptoms associated with blood cancer.

6. Stomach discomfort

Persistent abdominal discomfort, presenting as a sharp pain or a sense of feeling full.

7. Numbness in the hands or feet

This can be described as a feeling of pins and needles/numbness in the feet that moves up to the legs, or from fingers into the arms.

8. Heart palpitations

This can feel like a fluttering, a sudden thump or a fast pounding sensation in the chest. It can also be felt in the neck or ear when lying down.

9. Loss of concentration

There may be a prolonged or recurring inability to concentrate or focus, and people may describe this as feeling mentally drained or dizzy.

10. Sleep problems

Blood cancer patients may have continuous trouble falling asleep or staying asleep. This might result in a restless night's sleep causing a feeling of extreme tiredness.

11. Itchy skin

Persistent, irritable and itchy skin. This may be experienced all over the body, or in isolated spots. Again, this symptom often appears alongside other physical symptoms associated with blood cancer.

Get it checked

These symptoms are very common and don't automatically mean you have cancer. But if you notice any unusual or ongoing changes, it's always best to see your doctor and get checked out sooner rather than later.

Link:
Blood cancer symptoms everybody needs to know - The Irish News

Recommendation and review posted by Bethany Smith