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Sixty years ago this month, on April 22, 1964, the New York Worlds Fair opened in Flushing MeadowsCorona Park in Queens, New York. The Fair had the theme of Peace Through Understanding, and was dedicated to Mans Achievement on a Shrinking Globe in an Expanding Universe, as symbolized by the 140-foot-tall stainless-steel globe, known as the Unisphere, that towered over a massive reflecting pool.

The 1964 Worlds Fair wasnt the first one held in Flushing Meadows; the Unisphere was built on the same ground once occupied by the similarly spherical Perisphere, which was constructed for the 1939 Worlds Fair. To kick off the 1964 Fair, President Lyndon B. Johnson delivered opening remarks that evoked the 39 edition, which imagined the 1960s of the future:

But Johnsons reflections on human progress werent all positive. No one prophesied that half the world would be devastated by war, or that millions of helpless would be slaughtered, the President noted, just months after he approved the controversial National Security Action Memorandum 288 escalating the U.S.s involvement in the Vietnam War. No one foresaw power that was capable of destroying man, or a cold war which could bring conflict to every continent.

Overhead view of the 1964 Worlds Fair, showing the Unisphere and surrounding pavilions in Flushing Meadows-Corona Park in Queens, New York.

Johnsons presence at the 1964 Worlds Fair underscored the somber reality facing America at the time. After all, an assassins bullet killed the intended speaker, his predecessor, John F. Kennedy, thrusting hima representative of Washington D.C.s old guardinto the role intended for JFK, a symbol of the New Frontier.

So, who could Fair attendees turn to for hopeful visions of Peace Through Understanding, and Mans Achievement on a Shrinking Globe? Only one man: Walt Disney.

Disney, who had been a weekly presence in American homes for the last decade through his television show, Walt Disneys Disneylandlater titled Walt Disney Presentscreated four attractions for the 64 Worlds Fair. These exhibits were a hit, drawing 135,000 visitors per day during the first season alone, according to The Walt Disney Family Museum.

Walt Disney at the 1964 New York Worlds Fair

Visitors line up to enter Its A Small World at the Worlds Fair in 1965.

Disneys attractions included Great Moments with Mr. Lincoln at the Illinois Pavilion, an animatronic replica of another President who represented hope, and who was also assassinated; Fords Magic Skyway for the Ford Motor Company, where guests rode in Ford vehicles past animatronic dinosaurs; and the now-iconic its a small world, which Disneys Imagineers built in collaboration with Pepsi-Cola as a tribute to UNICEF.

But it was the Carousel of Progress, located in General Electrics Progressland pavilion, that most epitomized Walt Disneys vision of the future. The rotating animatronic show guided audiences through the history of human innovation and provided a comforting escape with its optimistic theme song by the Sherman Brothers, promising, Theres a great, big, beautiful tomorrow/Shining at the end of every day.

In the aftermath of a national tragedy, Walt Disney became a beacon of optimism for fairgoers, and for Americans. His presence fostered a belief in a great big beautiful tomorrow.

Perhaps its that enduring optimism that fuels the persistent conspiracy that Disney, who died in 1966, might still be among us, secretly preserved in hopes of one day being revived.

In 1964, besides contributing to the Worlds Fair, Disney also released his most acclaimed live-action film yet: Mary Poppins. Just a few years earlier, during a screening of To Kill a Mockingbird, Disney had reportedly lamented, Thats the kind of film Id like to make, but I cant. Now, his tender musical adaptation of P.L. Travers novel had achieved the same milestone as Universals adaptation of Harper Lees seminal work: a nomination for Best Picture at the Academy Awards.

Poster for Mary Poppins, touting the film as "Walt Disney's Greatest Achievement."

With his status finally solidified in the entertainment industry, Disney turned his sights to the futurenot of his film studio, but of humanity. Intent on using his renowned imagination to forge a brighter tomorrow, Disney envisioned a utopia designed to last forever. In 1964, the future looked bright for Walt Disney.

In less than three years, he would be dead.

On December 15, 1966, Walt Disney died as a result of complications from lung cancer. As Biography notes, a private funeral was held the next day, and on December 17, his body was cremated and interred at Forest Lawn Memorial Park in Glendale, California.

Some conspiracy theorists, however, believe that Disneys remains arent actually at Forest Lawn. Theyll tell you, according to Biography, that Disneys body is instead suspended in a frozen state and buried deep beneath the Pirates of the Caribbean ride at Disneyland in Anaheim, California, awaiting the day when medical technology would be advanced enough to reanimate the animator.

The rumored cryonic freezing of Walt Disney has no clear origin point that Biography could confirm. But its first documented mention is in a 1969 Ici Paris article, reportedly as a prank concocted by disgruntled animators who once worked for Disney seeking to have a laugh at their late taskmasker employers expense. Their motive was seemingly revenge for Disneys strict oversight, an aftermath of a labor uprising in the late 1930s that is chronicled in depth in The Disney Revolt: The Great Labor War of Animations Golden Age.

Initially, whispers suggested Disneys entire body was preserved in a secret facility, but soon the tale focused on the animators head alone, frozen beneath iconic Disneyland attractions like Pirates of the Caribbean, the Matterhorn, the Partners statue at the center of the park, and even the Magic Kingdom castle. Over time, it seems every corner of Disneyland has been rumored to shelter its founders frozen head.

The notion of Walt Disneys icy remains hiding within park attractions might stem from the actualsecrets of Disneyland. There is indeed a hidden space at the top of the Matterhorn, but its home to a basketball court for bored Disney staff, not a frozen former CEO. And while early versions of Pirates of the Caribbean did feature real skeletons from UCLAs medical school, according to SFGate, none belonged to Disney himself.

The grim idea that only Walt Disneys head was placed in cryostasis might have caught on due to its eerie, sci-fi feel, with modern cryonics offering both full-body and head-only preservation options. That singular detail adds a creepy wrinkle to the conspiracy, evoking images more akin to the 1962 horror flick The Brain That Wouldnt Die than the reality of a Hollywood moguls legacy.

Nevertheless, the tale of Walt Disneys frozen head persisted, specifically resurfacing in two biographies released years after his death: Leonard Moselys 1986 Disneys World and Marc Eliots 1993 Walt Disney: Hollywoods Dark Prince, which further embedded the legend into popular culture.

Eliots controversial biography, which was criticized by Disneys family and historians alike for its speculative content, included unfounded allegations against Disney, including claims that he was an FBI informant (which evidence suggests he was not), and that he refused to have flags at half mast at Disneyland when JFK died (which photographic evidence disproves). Nevertheless, Hollywoods Dark Prince fed into a desire to find the dark side of a man often propped up as the symbol of Americana, pushing both the cryonics rumor and the assertions of Disneys rampant antisemitism (also notably debunked) into the mainstream.

Disneys family has firmly denied the rumor that he was cryogenically frozen, and as Biography points out, it has been further discredited by those pointing to the existence of signed legal documents that indicate Disney was in fact cremated and that his remains are interred in a marked plot (for which his estate paid $40,000) at Forest Lawn, the exact location of which is a matter of public record. Plus, the first instance of a person being cryopreserved after his death, James Bedford, didnt occur until nearly a month after Disneys cremation, debunking the timeline of the rumor that Disney was frozen.

Walt Disneys grave site at Forest Lawn Memorial Park in Glendale, California.

Diane Disney, Walts daughter, wrote in a 1972 biography about her famous father that she doubted her father had even heard of cryonics.

Nonetheless, even skeptics who reject the frozen head story might concede that Walt Disney, a famously forward-thinking futurist, could have been aware of cryonics. The concept gained attention in 1964, the same year Disney shifted his focus from film to envisioning his utopian future.

If you were browsing the New Releases shelf at a bookstore in 1964, you might stumble upon an intriguing non-fiction book in between copies of Ernest Hemingways A Moveable Feast and the Warren Commissions The Warren Report: Robert Ettingers The Prospect of Immortality.

Most of us now living have a chance for personal, physical immortality, Ettinger claims in the very first sentence. All you need to do, Ettinger says, is join one established fact with one reasonable assumption.

The fact: At very low temperatures it is possible, right now, to preserve dead people with essentially no deterioration, indefinitely.

The assumption: If civilization endures, medical science should eventually be able to repair almost any damage to the human body, including freezing damage and senile debility or other cause of death.

Six decades later, while we havent mastered the art of repairing all human body damage, our cryopreservation methods have advanced significantly, particularly with the introduction of vitrification by Greg Fahy and William F. Rall in the 1980s. And recent scientific advancements suggest that what we currently understand as death might be more reversible than previously thought.

Some excerpts from Ettingers book resonate with the futuristic optimism of Walt Disneys Tomorrowland. For example, Ettinger writes,If civilization endures ... if the Golden Age materializes, the future will reveal a wonderful world indeed, a vista to excite the mind and thrill the heart. However, even if Disney had encountered Ettingers work, his imagination had already been sparked by another piece of literature before he died.

In May 1960, Horizon magazine published Out of a Fair, a City, an article in which architect Victor Gruen envisioned transforming the 1964 Worlds Fair site into a domed city to test solutions for societal challenges. According to Imagineer Marty Sklars 1999 book, Remembering Walt, Gruens philosophy (further elaborated in Gruens 1964 work, The Heart of our Cities: The Urban Crisis, Diagnosis and Cure,) was a significant influence on Disney during his final yearsso much that he began an ambitious plan to build a community in Florida that would never cease to be a living blueprint of the future.

Disney, utilizing land his corporation discreetly bought in Florida, set out to build an Experimental Prototype Community of Tomorrow adjacent to his planned East Coast theme park. The community aimed to eliminate traffic jams, offer abundant green spaces, and showcase efficient public transportation with the use of a monorail system.

EPCOT world showcase at Walt Disney World Resort, 1982

After Walt Disneys death, the Florida land earmarked for his future city was transformed into EPCOT, the second theme park at Walt Disney World Resort. EPCOT features a Future World section with educational attractions and a World Showcase with international pavilions, operating as a perpetual Worlds Fair.

In his last years, Walt Disney was introspective, focusing not on the prospect of immortality, but on a different sentiment. While the 1964 song Great Big Beautiful Tomorrow planted the seed in millions of young minds, it was another tune by the Sherman Brothers from the same year that resonated deeply with Disney as he reflected on his life. Richard Sherman recalls:

There is little left of the 1964 New York Worlds Fair in Flushing MeadowsCorona Park. The spot where the Carousel of Progress once played in GEs Progressland is now an athletic field. The Vatican pavilion has been replaced by a stone bench. The Unisphere, however, still remains, towering over a park whose occupants have little memory, or even awareness, of the Great Big Beautiful Tomorrow promised at the park 60 years ago.

The Unisphere in Flushing Meadows-Corona Park in March 2024.

For the Baby Boomers who experienced Disneys contributions to the 1964 Worlds Fair, the event offered hope and a last optimistic vision of the future from Uncle Walt. And while today, these visitors can encounter preserved pieces of the Fair at the Queens Museum and experience its a small world at Disney parks worldwide, they cant turn that athletic field back into Progressland. And they cant bring back the man who made it possible.

Walt Disney and Mickey Mouse at the Rose Parade in 1966.

Walt Disneys legacy extends far beyond his films and theme parks. He symbolizes something greater than a sprawling entertainment empire. As biographer Neal Gabler put it in the final pages of Walt Disney: The Triumph of the American Imagination, he demonstrated how one could assert ones will on the world at the very time when everything seemed to be growing beyond control and beyond comprehension.

For conspiracy theorists who want to believe Walt Disney is a frozen head, waiting for revival, perhaps its because they want to believe he asserted his will over the one thing no one has been able to do before. That maybe, if the Golden Age materializes, Walt Disney could even come back to life. And with him would come, once again, the promise of a Great Big Beautiful Tomorrow. A promise he made in Queens 60 years ago.

Michael Natale is the news editor for Best Products, covering a wide range of topics like gifting, lifestyle, pop culture, and more. He has covered pop culture and commerce professionally for over a decade. His past journalistic writing can be found on sites such as Yahoo! and Comic Book Resources, his podcast appearances can be found wherever you get your podcasts, and his fiction cant be found anywhere, because its not particularly good.

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The Truth About Walt Disney's Frozen Head and His Quest to Live Forever - Popular Mechanics

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Freezing your body after death with the hope of coming back to life one day sounds like something out of a science fiction movie.

Southern Cryonics, the first body-freezing facility in the Southern Hemisphere, tries to turn this idea into reality.

Were sort of in a race against time, says Southern Cryonics director, Peter Tsolakides, to Neos Kosmos.

Cryonics, coming from the Greek word kros for icy cold, involves the preservation of legally declared dead bodies at extremely low temperatures for potential future revival.

The facility in Holbrook, New South Wales, uses this practice, with the expectation that one day, advancements in medical technology and science will restore patients to health and in the young body.

But the timeframe of this future remains uncertain.

Tsolakides says once you preserve a body, you can keep it (stored) for thousands of years, but the chance of coming back depends on when you freeze it.

A matter of life after death

He says, currently 50 people, are willing to take the risk for a chance at life after death, and the number is growing.

This group consists of 35 investors each contributing $50,000 to $70,000, and 15 subscribers or customers who have paid $150,000 through life insurance.

Tsolakides says there are no guarantees, despite how great the dream of being brought back from the dead might be for some people.

Most of them know something about it (cryonics), but they also look at it and say, look, theres no guarantees, but theres a chance.

And that chance versus being buried in the ground or cremated is a much higher chance coming back.

He estimates the chance of a well-preserved body being revived in 200 years to be around 20%.

He says although its hard to predict what the world will be like in be like in 1,000 years, bodies might be revived when technological advancements have found the key to immortality.

In the real world, nobody will be dying, and most diseases will be cured. So, we will know how to prevent death in a sense, and the next step is to bring back those who have already died, but in a good condition.

Tsolakides says that while they dont know how to bring a person back to life, current developments give you inklings, of what the future is going to be like.

He says progress has to start somewhere, and right now billions are invested in medical research aimed at disease cures.

This includes groups working on brain revival, organ regeneration, cloning, and advancements in artificial intelligence and nanotechnology.

How does cryonics work?

When a person is declared legally dead at the hospital, a cooling process begins.

Chemicals are used to stabilise the body, lowering it to about ice temperature.

Once taken to the funeral home, the body is further cooled and infused with an antifreeze substance until it reaches about -80C.

Next, it goes to the cryonics facility, gradually cooled to -180C and preserved below that temperature, in a large vacuum flask container filled with liquid nitrogen.

Southern Cryonics Greek-Australian director says, theres a brief window of a few hours after legal death, where no deterioration occurs to the body.

Once preserved in liquid nitrogen, it can be stored for thousands of years due to almost no chemical or biological activity at that temperature.

Its a race against time to keep the temperature going down, he says.

But is it possible to freeze a human brain to revive it later?

If you catch them (bodies) under our optimal time, very little damage is occurring to the brain, but that doesnt mean that 200 years from now, that damage cant be repaired, Tsolakides says.

The facility can currently hold up to 40 patients, with each container fitting 4 bodies, but can expand to hold up to six or seven hundred patients if necessary.

The birth and evolution of Southern Cryonics

Tsolakides got interested in cryonics from a young age.

When he came back to Australia around 2012 after working overseas, he saw there were only cryonics facilities in the US and Russia.

He connected with like-minded people and talked about building one in Australia.

We started getting what we call founding members, says Tsolakides, each contributing $50,000 to kickstart the project, eventually totalling 35 members of a non-profit organisation.

We started the facility and that was how it sort of developed.

He says, they chose Holbrook, a small town with about 1,500 people, for a few reasons.

Land there wasnt expensive, and it was halfway between Melbourne and Sydney, making it accessible to over half of Australias population.

Holbrooks nearby Albury airport is crucial for quick patient transportation, and the support from the local council made the decision easier.

Another advantage is its proximity to liquid nitrogen suppliers along the Hume Highway, crucial for the facility.

Holbrooks low history of natural disasters made it a safe choice after a thorough analysis of several years.

The legalities

Tsolakides says Southern Cryonics got all the official approvals from the NSW Department of Health and the local council, to operate as a cemetery but uses a recognised funeral home for mortuary work.

The government groups that we work with helped us a lot. It wasnt like we got resistance or anything like that.

A good idea but not for everyone

Tsolakides was born in Israel to Greek parents.

His mother was from the Greek island of Syros, and his father from Athens.

They briefly lived in Greece before moving to Australia in 1955 when Tsolakides was five years old.

He has a degree in Chemistry and later pursued one in Business Administration.

Throughout his career, he worked primarily in marketing for an oil company.

He grew up and lived in Melbourne for many years before moving to Sydney, a place he now calls home.

His passion in cryonics sparked at about18 after reading Robert Ettingers book, The Prospect of Immortality.

At that age, he didnt worry much about death.

He assumed this will be everywhere, by the time he got old, but soon realised that very few people worldwide were interested in it.

He says that while some are intrigued by cryonics, most view it as a good idea but not for themselves.

Even the US organisation have about five to six thousand members only, with 400 or 500 people suspended, and theyve been going for 50 years.

But that didnt stop him for pursuing his curiosity around cryonics.

Keeping an eye on scientific developments

Tsolakides is determined to improve their techniques and increase success chances, despite challenges or doubts about cryonics.

He says Southern Cryonics along with overseas organisations is monitoring the best way to store a body, leaving the revival work to other scientists.

Its (suspending the body) physically possible to do it now, he says, but of course, you can always improve the processes.

While cryonics remains a controversial field and the chances of revival seem low now, it is yet to be seen whether future technology will ever be able to bring the dead back to life.

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Is it possible to come back from the dead? Australia's first body-freezing facility explores the boundaries of mortality - Neos Kosmos

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The following is a summary of Effect of Testosterone Replacement Therapy on Sexual Function and Hypogonadal Symptoms in Men with Hypogonadism, published in the February 2024 issue of Endocrinology by Pencina, et al.

For a Testosterone Replacement Therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) study, researchers sought to assess the efficacy of testosterone replacement therapy (TRT) in improving sexual function and hypogonadal symptoms in men with hypogonadism, with a focus on whether these effects are sustained beyond 12 months. The Sexual Function Study, nested within the TRAVERSE trial, specifically evaluated the impact of TRT on sexual activity, hypogonadal symptoms, libido, and erectile function among men with low libido.

Among 5,204 men aged 45-80 years with two testosterone concentrations <300 nag/dL, hypogonadal symptoms, and cardiovascular disease (CVD) or increased CVD risk enrolled in the TRAVERSE trial, 1,161 participants with low libido were included in the Sexual Function Study. Of these, 587 were randomized to receive 1.62% testosterone gel and 574 to placebo gel for their participation. The primary outcome was the change from baseline in sexual activity score, with secondary outcomes including hypogonadal symptoms, erectile function, and sexual desire.

TRT was associated with a significantly greater improvement in sexual activity compared to placebo, with a sustained treatment effect observed at 24 months. Additionally, TRT improved hypogonadal symptoms and sexual desire, although it did not significantly affect erectile function compared to placebo.

In middle-aged and older men with hypogonadism and low libido, TRT for 2 years effectively improved sexual activity, hypogonadal symptoms, and sexual desire. However, it did not demonstrate significant improvements in erectile function compared to placebo.

Reference: academic.oup.com/jcem/article-abstract/109/2/569/7244351

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Enhancing Quality of Life: Testosterone Replacement Therapy for Hypogonadal Men - Physician's Weekly

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CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy | Cancer Gene Therapy - Nature.com

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The discovery of Clustered Regularly Interspaced Short Palindromic Repeats (widely known as just CRISPR) has been revolutionary in many ways. For one, it has transformed disease research. Just recently, scientists revealed they could cut HIV out of cells using the gene-editing technology, and it also has the potential to completely change the way cancer is treated, too. But CRISPRs abilities dont end there. It could also change the way that food tastes (making healthier foods more appealing to children, for example), and even save the food system from the brutal impact of the climate crisis.

Right now, extreme weather events, including drought, heatwaves, and floods, threaten essential crops all over the world. In fact, one 2021 study from NASA suggested that the impact of global climate change could impact crops within the decade. Maize yields are a particular concern, as the research suggested they could drop by 24 percent. A 20 percent decrease from current production levels could have severe implications worldwide, Jonas Jgermeyr, crop modeler and climate scientist, said at the time.

But, by improving their resilience, CRISPR could help to save more crops from falling foul to extreme weather events, which, as the human-driven climate crisis intensifies, are only set to become more common over the coming years.

Pexels

CRISPR is, essentially, a revolutionary gene-editing technology. Adapted from a naturally occurring defense mechanism found in bacteria, the system enables scientists to make precise changes to the DNA of organisms. In 2020, Emmanuelle Charpentier and Jennifer Douda were awarded the Nobel Prize in Chemistry for pioneering CRISPR-Cas9. The technology is also known as genetic scissors, because of the way it can help researchers cut DNA.

The statement from The Nobel Prize at the time noted that, since 2012, when Charpentier and Doudna first discovered the CRISPR-Cas9 genetic scissors, it has contributed to many important discoveries in basic research, adding that as well as leading to major breakthroughs in curing inherited diseases, plant researchers have been able to develop crops that withstand mold, pests, and drought.

In terms of crops, CRISPR can help scientists change and insert DNA into plants to make them more resistant to harsher surroundings. It could help make them less vulnerable to extreme temperatures, for example, and even help increase crop yield to produce more food for more people.

Pexels

CRISPR is already helping scientists to overcome major challenges in the food system. In January 2024, for example, a paper published in Nature revealed that researchers in Kenya are working on making sorghuma staple food across many African countriesmore resilient to a parasitic weed, called Striga, using the gene-editing technology.

In Singapore, a company called Singrow launched the worlds first climate-resilient strawberry last year, which was also created with the help of CRISPR. In North Carolina, the scientists behind the food startup Pairwise are developing more nutritious crops, produce higher yields, and require fewer resources to grow with the technology. Earlier this year, the company was even acknowledged by Time Magazine as one of Americas Top Greentech Companies.

These companies are far from alone. According to the food innovation platform Forward Fooding, more than 50 companies around the world are currently using DNA technology to improve crops. It notes that since 2013, they have raised around 2.3 billion in funding.

CRISPR is not perfect. Its important to note that this technology is still new, and more research is needed into the long-term effects of gene-editing crops. But so far, the progress is promising.

As well as a move away from animal agriculture, which is widely considered by scientists to be depleting the earth of natural resources and driving up emissions, CRISPR could be one of the key factors in building a more sustainable, resilient, nutritious food system, which may also be able to feed more people than ever.

Charlotte is a writer and editor based in sunny Southsea on England's southern coast.

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Revolutionary CRISPR Technology Is Helping Make Crops More Resilient to the Climate Crisis - VegNews

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Greater use of CRISPR-based therapies in clinical trials is expected to drive further advancements in precision medicine, GlobalData states.

There has been a notable rise in licensing agreements for innovator drugs incorporating clustered regularly interspaced short palindromic repeats (CRISPR)-based technology for gene therapies over the past five years, according to data and analytics firm GlobalData.

These agreements have amassed a total deal value of $21 billion. Of note, between 2020 to 2022, there was a remarkable surge in deal worth. For agreements relating to or involving treatments for haematological disorders, the total deal value reached $1.8 billion, the research found.

For instance, the approval of Casgevy in the US in December 2023 signified a breakthrough in gene therapy. Vertex Pharmaceuticals treatment was subsequently the first CRISPR/Cas9 gene-edited therapy to be granted a marketing authorisation by the European Commission (EC) in February 2024.

Innovator drugs harnessing CRISPR technologies saw 182 percent growth in total licensing agreement deal value from $5.6 billion in 2020 to $15.8 billion in 2022. Among the top three therapy areas, oncology represented over half of the total deal value with $11.9 billion, followed by immunology with $6.7 billion, and central nervous system with $2.2 billion, Ophelia Chan, Business Fundamentals Analyst at GlobalData explained.

GlobalData highlighted that the largest CRISPR-based deal of 2023 was Eli Lilys subsidiary, Prevail Therapeutics gaining rights to Scribe Therapeuticss CRISPR X-Editing (XE) technologies. In a deal potentially worth over $1.57 billion, the agreement seeks to advance in vivotherapies for targets that cause serious neurological and neuromuscular diseases.

The increasing presence of CRISPR-based therapies in clinical trials is anticipated to fuel further advancements in precision medicine

CRISPR technology is transforming targeted gene therapies for diverse unmet diseases by precisely targeting diverse genomic sites, promising tailored treatments and improved patient outcomes. The increasing presence of CRISPR-based therapies in clinical trials is anticipated to fuel further advancements in precision medicine, Chan stated.

In other recent gene therapy news, last month the US Food and Drug Administration (FDA) authorised Lenmeldy (atidarsagene autotemcel) for children with early-onset metachromatic leukodystrophy (MLD).

Anti-Cancer Therapeutics, Big Pharma, Biopharmaceuticals, business news, Clinical Development, Clinical Trials, Data Analysis, Drug Development, Drug Markets, Drug Safety, Gene therapy, Industry Insight, Research & Development (R&D), Technology, Therapeutics

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CRISPR technologies fuelling haematological innovations - European Pharmaceutical Review

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Kelly Banas, Ph.D., principal investigator at ChristianaCares Gene Editing Institute, will present her latest research discovery related to targeting the NRF2 gene in cancer cells at the first CRISPR Medicine Conference held in Copenhagen, Denmark, April 22 to 25. The Gene Editing Institutes research has focused on the NRF2 gene and the strong immune response []

The post Kelly Banas, Ph.D., To Present Her Latest Discovery at CRISPR Medicines First International Conference appeared first on ChristianaCare News.

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Fort Lauderdale, FL, April 09, 2024 (GLOBE NEWSWIRE) -- The adage age is just a number embodies feeling young at any age. So whats more important when it comes to healthy aging: brain or brawn? In a recent survey of 4,100 Life Extension customers, 68% of whom were aged 61 or older, more than half ranked mental performance as the most important factor for feeling young for their age, while physical health came in a distant second place at 24%. To help people stay ahead of the aging game, Life Extension has launched Healthy Aging Powder, a triple-nutrient blend of taurine for cardiovascular health, lithium for a healthy mood, and spermidine from wheat germ extract to promote memory health. February 2024 survey of Life Extension customers.

We wanted to offer customers a way to promote a healthy aging process, so we focused on finding nutrients that support three cornerstones of aging gracefully: memory and mood health and a healthy heart, explained Life Extensions Vice President of Product Development, Glenn MacEachern, MBA.

According to Michael A. Smith, MD, Life Extensions Director of Education, aging healthily goes beyond flexing strong muscles; it also depends on heart health and, yes, cognition. Physical health is a no-brainer when it comes to healthy aging, but many dont realize that maintaining cognitive health and performance, including a healthy mood, is also crucial, Dr. Smith said. Weve come to accept our working memory slowing down and our mood souring as the norm. But we dont have to take age-related cognitive decline for granted. By tweaking our lifestyle, we can support memory health and maintain a healthy mood at every age.

Dr. Smith recommends choosing a dietary supplement that addresses the trifecta of healthy agingmemory and mood health, and a healthy heartas a proactive way to make those later years truly golden.

Healthy Aging Powder is a new addition to Life Extensions longevity supplements line, which also includes Optimized Resveratrol Elite to help protect against oxidative stress and NAD+ Cell Regenerator to support healthy cellular energy pathways. The easy-mix, unflavored powder blend contains no genetically modified ingredients.

About Life Extension For more than 40 years, Life Extension has pursued innovative advances in health, conducting rigorous clinical trials and setting some of the most demanding standards in the industry to offer a full range of quality vitamins and nutritional supplements and blood-testing services. Life Extensions Wellness Specialists provide personalized counsel to help customers choose the right products for optimal health,nutritionand personal care. To learn more, visit LifeExtension.com.

These statements have not been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease.

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Mental Performance Is the #1 Factor for Healthy Aging, According to Life Extension Survey - GlobeNewswire

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Overview

The human body regenerates itself constantly, replacing old, worn-out cells with a continuous supply of new ones in almost all tissues. The secret to this perpetual renewal is a small but persistent supply of stem cells, which multiply to replace themselves and also generate progeny that can differentiate into more specialized cell types. For decades, scientists have tried to isolate and modify stem cells to treat disease, but in recent years the field has accelerated dramatically.

A major breakthrough came in the early 21st century, when researchers in Japan figured out how to reverse the differentiation process, allowing them to derive induced pluripotent stem (iPS) cells from fully differentiated cells. Since then, iPS cells have become a cornerstone of regenerative medicine. Researchers can isolate cells from a patient, produce iPS cells, genetically modify them to repair any defects, then induce the cells to form the tissue the patient needs regenerated.

On April 26, 2019, the New York Academy of Sciences and Takeda Pharmaceuticals hosted the Frontiers in Regenerative Medicine Symposium to celebrate 2019 Innovators in Science Award winners and highlight the work of researchers pioneering techniques in regenerative medicine. Presentations and an interactive panel session covered exciting basic research findings and impressive clinical successes, revealing the immense potential of this rapidly developing field.

Shinya Yamanaka Kyoto University

Shruti Naik New York University

Michele De Luca University of Modena and Reggio Emilia

Masayo Takahashi RIKEN Center for Biosystems Dynamics Research

Hiromitsu Nakauchi Stanford University and University of Tokyo

Brigid L.M. Hogan Duke University School of Medicine

Emmanuelle Passegu Columbia University Irving Medical Center

Hans Schler Max Planck Institute for Molecular Biomedicine

Austin Smith University of Cambridge

Moderator: Azim Surani University of Cambridge

Shinya Yamanaka Kyoto University

Shinya Yamanakaof Kyoto University, gave the meetings keynote presentation, summarizing his laboratorys recent work using induced pluripotent stem (iPS) cells for regenerative medicine. The first clinical trial using iPS cells to treat age-related macular degeneration started five years ago. In his clinical trial, physicians isolated somatic cells from a patient, then used developed culture techniques to derive iPS cells from them. iPS cells can proliferate and differentiate into any type of cell in the body, which can then be transplanted back into the patient. Experiments over the past five years have shown that this approach has the potential to treat diseases ranging from age-related macular degeneration to Parkinsons disease.

However, this autologous transplantation strategy is slow and expensive. It takes up to a year just evaluating one patient, [and] it costs us almost one million US dollars, said Yamanaka. Before transplanting the differentiated cells, the researchers evaluated the entire iPS cell derivation and iPS cell differentiation processes, adding to time and cost. As another strategy, Yamanakas team is working on the iPS Cell Stock for Regenerative Medicine. Here, iPS cells are derived from blood cells of healthy donors, not the patients, and are stocked. The primary problem with this approach is the human leukocyte antigen (HLA) system, which encodes multiple cell surface proteins. Each person has a specific combination of HLA genes, or haplotype, defining the HLA proteins expressed on their own cells. The immune system recognizes and eliminates any cell expressing non-self HLA proteins. Because there are millions of potential HLA haplotypes, cells derived from one person will likely be rejected by another.

The homozygous superdonor cell line has limited immunological diversity, allowing it to match multiple patients.

To address that, Yamanaka and his colleagues are collaborating with the Japanese Red Cross to develop superdonor iPS cells. These cells carry homozygous alleles for different human lymphocyte antigen (HLA) genes, limiting their immunological diversity and making them match multiple patients. So far, the team has created four superdonor cell lines, allowing them to generate cells compatible with 40% of the Japanese population. Those cells are now being used in clinical trials treating macular degeneration and Parkinsons disease, with more indications planned.

So far so good, said Yamanaka, but he added that in order to cover 90% of the Japanese population we would need 150 iPS cell lines, and in order to cover the entire world we would need over 1,000 lines. It took the group about five years to generate the first four lines, so simply repeating the process that many more times isnt practical.

Instead, Yamanaka hopes to take the HLA reduction a step further, knocking out most of the major HLA genes to generate cells that will survive in large swaths of the population. However, simply knocking out entire families of genes isnt enough. Natural killer cells attack cells that are missing particular cell surface antigens, so the researchers had to leave specific markers in the cells, or reintroduce them transgenically. Natural killer and T cells from various donors ignore leukocytes derived from these highly engineered iPS cells, proving that the concept works. With this approach, just ten lines of iPS cells should yield a range of donor cells suitable for any human HLA combination. Yamanaka expects these gene-edited iPS cells to be available in 2020.

By 2025, Yamanaka hopes to announce my iPS cell technology. This technology will reduce the cost and time for autologous transplantation to about $10,000 and one month per patient.

While preclinical and early clinical trials on iPS cells have yielded promising results, the new therapies must still cross the valley of death, the pharmaceutical industrys term for the unsuccessful transition and industrialization of innovative ideas identified in academia to routine clinical use. In an effort to make that process more reliable, Yamanaka and his colleagues have begun a unique collaboration with Takeda Pharmaceutical Company Limited, Japans largest drug maker. The effort involves 100 scientists, 50 each from the company and academic laboratories. The corporate researchers gain access to the latest basic science developments on iPS cell technology, while the academics can use the companys cutting-edge R&D know-how equipment and vast chemical libraries.

In one project, the collaborators used iPS cells to derive pancreatic islet cells, and then encapsulated the cells in an implantable device to treat type 1 diabetes. The system successfully decreased blood glucose in a mouse model, and the team is now scaling up cell production to test it in humans in the future. Another effort identified chemicals in Takedas compound library that speed cardiomyocyte maturation, which the researchers are now using to improve iPS cell-derived treatments for heart failure. In a third project, the team has modified iPS cell-derived T cells to identify and attack tumors, again showing promising results in a mouse model.

Shruti Naik New York University

Michele De Luca University of Modena and Reggio Emilia

Shruti Naik, Early-Career Scientist winner of the 2019 Innovators in Science Award, discussed her work on epithelial barriers. These barriers, which include skin and the linings of the gut, lungs, and urogenital tract, exhibit nuanced responses to the many microbes they encounter. Injuries and pathogenic infections trigger prompt inflammatory responses, but the millions of harmless commensal bacteria that live on these surfaces dont. How does the epithelium know the difference?

To ask that question, Naik first studied germ-free mice, which lack all types of bacteria. These animals have defective immune responses against pathogens that affect epithelia, so commensal bacteria are clearly required for developing normal epithelial immunity. Naik inoculated the germ-free mice with bacterial strains found either on the skin or in the guts of normal mice, then assessed their immune responses in those two compartments.

When you gave gut-tropic bacteria, you were essentially able to rescue immunity in the gut but not the skin, and conversely when you gave skin-tropic bacteria, you were able to rescue immunity in the skin and not the gut, said Naik. Even though the commensal bacteria caused no inflammation, they did activate certain T cells in the epithelia they colonized, apparently preparing those tissues for subsequent attacks by pathogens.

Next, Naik took germ-free mice inoculated with Staphylococcus epidermidis, a normal skin commensal bacterium, and challenged them with an infection by Candida albicans, a pathogenic yeast. The bacterially primed mice produced a much more robust immune response against the yeast infection than control animals that hadnt gotten S. epidermidis. Naik confirmed that this immune training effect operates through the T cell response shed seen before. You essentially develop an immune arsenal to your commensals that helps protect against pathogens, Naik explained, adding that each epithelial barrier requires its own commensal bacteria to trigger this response.

Augmented wound repair in post-inflammation skin reveals that naive and inflammation-educated skin stem cells respond differently to subsequent stresses.

The response to epithelial commensals is remarkably durable; Naik found that the skin T cells in the inoculated mice remained on alert a year after their initial activation. That led her to wonder whether non-hematopoietic cells, especially epithelial stem cells, contribute to immunological memory in the skin.

To probe that, Naik and a colleague used a mouse model in which the topical drug imiquimod induces a temporary psoriasis-like skin inflammation. By tracing the lineages of cells in the animals skin, the researchers found that epithelial stem cells expand during this inflammation, and then persist. Challenging the mice with a wound one month after the inflammation resolves leads to faster healing than if the mice hadnt had the inflammation. Several other models of wound healing yielded the same result. The investigators concluded that naive and inflammation-educated skin stem cells respond differently to subsequent stresses.

Naiks team found that inflammation causes persistent changes in skin stem cells chromatin organization. Using a clever reporter gene assay, they demonstrated that the initial inflammation leaves inflammatory gene loci more open in the chromatin, making them easier to activate after subsequent insults. What was really surprising to us was that this change never fully resolved, said Naik. Even six months after the acute inflammation, skin stem cells retained the distinct post-inflammatory chromatin structure and the ability to heal wounds quickly. This chronic ready-for-action state isnt always beneficial, though. Naik noticed that the mice that had had the inflammatory treatment were more prone to developing tumors, for example.

In establishing her new laboratory, Naik has now turned her focus to another aspect of epithelial immunity: the link between immune responses and tissue regeneration. She looked first at a type of T cells found in abundance around hair follicles on skin. Mice lacking these cells exhibit severe delays in wound healing, apparently as a result of failing to vascularize the wound area. That implies a previously unknown role for inflammatory T cells in vascularization, which Naik and her lab are now probing.

Michele De Luca, Senior Scientist winner of the 2019 Innovators in Science Award, has developed techniques for regenerating human skin from transgenic epidermal stem cells. Researchers first isolated holoclones, or cells derived from a single epidermal stem cell, over 30 years ago. These cells can be used to grow sheets of skin in culture for both research and clinical use, but scientists have only recently begun to elucidate how the process works.

The first stem cell-derived therapies tested in humans were for skin and eye burns, allowing doctors to regenerate and replace burned epidermal tissue from a patients own stem cells. Thats the basis of Holoclar, a stem cell-based treatment for severe eye burns approved in Europe in 2015.

Holoclar and similar procedures work well for injured patients with normal epithelia. We wanted to genetically modify those cells in order to address one of the most important genetic diseases in the dermatology field, which is epidermolysis bullosa (EB), a devastating skin disease, said De Luca. In EB, patients carry a genetic defect in cell adhesion that causes severe blisters all over their skin and prevents normal healing. A large number of EB patients die as children from the resulting infections, and those who survive seldom get beyond young adulthood before succumbing to squamous cell carcinomas.

De Luca developed a strategy to isolate stem cells from a skin biopsy, repair the genetic defect in these cells with a retroviral vector, and then grow new skin in culture that can be transplanted back to the patient, replacing their original skin with genetically repaired skin. In 2015, the researchers carried out the procedure on a young boy named Hassan, who had arrived in the burn unit of a German hospital with EB after fleeing Syria. The burn unit was only able to offer palliative care, and his prognosis was poor because of his constant blistering and infections. De Lucas team received approval to perform their gene therapy on him.

The new strategy, which combines cell and gene therapy, resulted in the restoration of normal skin adhesion in Hassan.

After isolating and modifying epidermal stem cells from Hassan and growing new sheets of skin in culture, De Lucas team re-skinned the patients arms and legs, then his abdomen and back. The complete procedure took about three months. The new skin resists blister formation even when rubbed and heals normally from minor wounds. In the ensuing three and a half years, Hassan has begun growing normally and living an ordinary, healthy life.

Detailed analysis of skin biopsies showed that Hassans epidermis has normal cellular adhesion machinery and revealed that his skin is now derived from a population of proliferating transgenic stem cells, with no single clone dominating. By tracing the lineages of cells carrying the introduced transgene, De Luca was able to identify self-renewing transgenic stem cells, intermediate progenitor cells, and fully differentiated stem cells, indicating normal skin growth and replacement.

Besides being good news for the patient, the results confirmed a longstanding theory of skin regeneration. These data formally prove that the human epidermis is sustained only by a small population of long-lived stem cells that generates [short-lived epithelial] progenitors, said De Luca, adding that with this in mind, weve started doing other clinical trials.

The researchers plan to continue targeting junctional as well as dystrophic forms of EB, both of which are genetically distinct from EB simplex. Initial experiments revealed that in these conditions, transplant recipients developed mosaic skin, where some areas continued to be produced from cells lacking the introduced genetic repair. The non-transgenic cells appeared to be out-competing the transgenic cells and supplanting them, undermining the treatment. De Luca and his colleagues developed a modified strategy that gave the transgenic cells a competitive advantage. This approach and additional advances should allow them to achieve complete transgenic skin coverage.

Masayo Takahashi RIKEN Center for Biosystems Dynamics Research

Hiromitsu Nakauchi Stanford University and University of Tokyo

Masayo Takahashi, of RIKEN Center for Biosystems Dynamics Research, began her talk with a brief description of the new Kobe Eye Center, a purpose-built facility designed to house a complete clinical development pipeline dedicated to curing eye diseases. Not only cells, not only treatments, but a whole care system is needed to cure the patients, said Takahashi. In keeping with that philosophy, the Center includes everything from research laboratories to a working eye hospital and a patient welfare facility.

Takahashis recent work has focused on treating age-related macular degeneration (AMD). In AMD, the retinal pigment epithelium that nourishes other retinal cells accumulates damage, leading to progressive vision loss. AMD is the most common cause of serious visual impairment in the elderly in the US and EU, and there is no definitive treatment. Fifteen years ago, Takahashi and her colleagues derived retinal pigment epithelial cells from monkey embryonic stem cells and successfully transplanted them into a rat model of AMD, treating the condition in the rodents. They were hesitant to extend the technique to humans, though, because it required suppressing the recipients immune response to prevent them from rejecting the monkey cells.

The advent of induced pluripotent stem (iPS) cell technology pointed Takahashi toward a new strategy, in which she took cells from a patient, derived iPS cells from them, and then prompted those cells to differentiate into retinal pigment epithelial cells that were perfectly compatible with the patients immune system. Her team then transplanted a sheet of these cells into the patient. That experiment, in 2014, was the first clinical use of iPS cells in humans. The grafted cells were very stable, said Takahashi, who has checked the graft in multiple ways in the ensuing years.

Having proven that iPS cell-derived retinal grafts can work, Takahashi and her colleagues sought to make the procedure cheaper and faster. Creating customized iPS cells from each patient is a huge undertaking, so instead the team investigated superdonor iPS cells that can be used for multiple patients. These cells, described by Shinya Yamanaka in his keynote address, express fewer types of human leukocyte antigens than most patients, making them immunologically compatible with large swaths of the population. Just four lines of superdonor iPS cells can be used to derive grafts for 40% of all Japanese people.

Transplantation of an iPS cell-derived sheet into the retina ultimately proved successful.

In the next clinical trial, Takahashis lab performed several tests to confirm that the patients immune cells would not react with the superdonor cells, before proceeding with the first retinal pigment epithelial graft. Nonetheless, after the graft the researchers saw a minuscule fluid pocket in the patients retina, apparently due to an immune reaction. Clinicians immediately gave the patient topical steroids in the eye to suppress the reaction. Then after three weeks or so, the reaction ceased and the fluid was gone, so we could control the immune reaction to the HLA-matched cells, said Takahashi. Four subsequent patients showed no reaction whatsoever to the iPS superdonor-derived grafts.

While the retinal grafts were successful, none of the patients have shown much improvement in visual acuity so far. Takahashi explained that subjects in the clinical trial all had very severe AMD and extensive loss of their eyes photoreceptors. I think if we select the right patients, we could get good visual acuity if their photoreceptors still remain, said Takahashi.

Takahashi finished with a brief overview of her other projects, including using aggregates of iPS cells and embryonic stem cells to form organoids, which can self-organize into a retina. She hopes to use this system to develop new therapies for retinitis pigmentosa, another major cause of vision loss. Finally, Takahashi described a project aimed at reducing the cost and increasing the efficacy of stem cell therapies even further by employing a sophisticated laboratory robot. The system, called Mahoro, is capable of learning techniques from the best laboratory technicians, then replicating them perfectly. That should make stem cell culturing procedures much more reproducible and significantly reduce the cost of deploying new therapies.

Hiromitsu Nakauchi, of Stanford University and the University of Tokyo, described his groups efforts to overcome a decades-old challenge in stem cell research. Scientists have known for over 25 years that all of the blood cells in a human are renewed from a tiny population of multipotent, self-renewing hematopoietic stem cells. In an animal thats had all of its hematopoietic lineages eliminated by ionizing radiation, a single such cell can reconstitute the entire blood cell population. This protocol is the basis for several experimental models.

In theory, then, a single hematopoietic stem cell should also be able to multiply indefinitely in pure culture, allowing researchers to produce all types of blood cells on demand. In practice, cultured stem cells inevitably differentiate and die off after just a few generations in culture. Nakauchi and his colleagues have been trying to fix that problem. After years of hard work, we decided to take the reductionist approach and try to define the components that we use to culture [hematopoietic stem cells], said Nakauchi.

The team focused on the most undefined component of their culture media: bovine serum albumin (BSA). This substance, a crude extract from cow blood, has been considered an essential component of growth media since researchers first managed to culture mammalian cells. However, Nakauchis lab found tremendous variation between different lots of BSA, both in the types and quantities of various impurities in them and in their efficacy in keeping stem cells alive. Worse, factors that appeared to be helpful to the cells in some BSA lots were harmful when present in other lots. So this is not science; depending on the BSA lot you use, you get totally different results, said Nakauchi.

Next, the researchers switched to a recombinant serum albumin product made in genetically engineered yeast. That exhibited less variation between lots, and after optimizing their culture conditions they were able to grow and expand hematopoietic stem cells for nearly a month. Part of the protocol they developed was to change the medium every other day, which they found was required to remove inflammatory cytokines and chemokines being produced by the stem cells. That suggested the cells were still under stress, perhaps in response to some of the components of the recombinant serum albumin.

Polyvinyl alcohol can replace BSA in culture medium.

The ongoing problems with serum albumin products led Nakauchi to ask why albumin is even necessary in tissue culture. Scientists have known for decades that cells dont grow well without it, but why not? While trying to figure out what the albumin was doing for the cells, Nakauchis lab tested it against the most inert polymer they could find: polyvinyl alcohol (PVA). Best known as the primary ingredient for making school glue, PVA is also used extensively in the food and pharmaceutical industries. To their surprise, hematopoietic stem cells grew better in PVA-spiked medium than in medium with BSA. The PVA-grown cells showed decreased senescence, lower levels of inflammatory cytokines, and better growth rates.

In long-term culture, Nakauchi and his colleagues were able to achieve more than 900-fold expansion of functional mouse hematopoietic stem cells. Transplanting these cells into irradiated mice confirmed that the cells were still fully capable of reconstituting all of the hematopoietic lineages. Further experiments determined that PVA-containing medium also works well for human hematopoietic stem cells.

Besides having immediate uses for basic research, the ability to grow such large numbers of hematopoietic stem cells could overcome a fundamental barrier to using these cells in the clinic. Current hematopoietic stem cell therapies require suppressing or destroying a patients existing immune system to allow the transplanted cells to become established, but this immunosuppression can lead to deadly infections. Transplanting a much larger population of stem cells can overcome the need for immunosuppression, but growing enough cells for this approach has been impractical. Using their new culture techniques, Nakauchis team can now produce enough hematopoietic stem cells to carry out successful transplants without immunosuppression in mice. They hope to take this approach into the clinic soon.

Brigid L.M. Hogan Duke University School of Medicine

Emmanuelle Passegu Columbia University Irving Medical Center

Hans Schler Max Planck Institute for Molecular Biomedicine

Austin Smith University of Cambridge

Moderator: Azim Surani University of Cambridge

Austin Smith, from the University of Cambridge, gave the final presentation, in which he discussed his studies on the progression of embryonic stem cells through development. In mammals, embryonic development begins with the formation of the blastocyst. In 1981, researchers isolated cells from murine blastocysts and demonstrated that each of them can grow into a complete embryo. Stem cells isolated after the embryo has implanted itself into the uterus, called epiblast stem cells, have lost that ability but gained the potential to differentiate into multiple cell lineages in culture. So we have two different types of pluripotent stem cells in the mouse, and theyre different in just about every way you could imagine, said Smith.

Work on other species, including human cells, suggests that this transition between two different types of stem cells is a common feature of mammalian development. The transition from the earlier to the later type of stem cell is called capacitation. To find the factors driving capacitation, Smith and his colleagues looked for differences in gene transcription patterns and chromatin organization during the process, in both human and murine cells. What they found was a global re-wiring of nearly every aspect of the cells physiology. Together these things lead to the acquisition of both germline and somatic lineage competence, and at the same time decommission that extra-embryonic lineage potential, Smith explained.

Having characterized the cells before and after capacitation, the researchers wanted to isolate cells from intermediate stages of the process to understand how it unfolds. To do that, they extracted cells from mouse embryos right after implantation, then grew them in culture conditions that minimized their exposure to signals that would direct them toward specific lineages. Detailed analyses of these cells, which Smith calls formative stem cells, shows that they have characteristics of both the naive embryonic stem cells and the later epiblast stem cells. Injecting these cells into mouse blastocysts yields chimeric mice carrying descendants of the injected cells in all their tissues. The formative stem cells can therefore function like true embryonic stem cells, albeit less efficiently.

The developmental sequence of pluripotent cells.

Post-implantation human embryos arent available for research, but Smiths team was able to culture naive stem cells and prompt them to develop into formative stem cells. These cells exhibit transcriptional profiles and other characteristics homologous to those seen in the murine formative stem cells.

Having found the intermediate cell type, Smith was now able to assemble a more detailed view of the steps in development. Returning to the mouse model, he compared the chromatin organization of naive embryonic, formative, and epiblast stem cells. The difference between the naive and formative cells chromatin was much more dramatic than between the formative and epiblast cells.

Based on the results, Smith proposes that naive embryonic stem cells begin as a blank slate, which then undergoes capacitation to become primed to respond to later differentiation signals. The capacitation process entails a dramatic change in the cells transcriptional and chromatin organization and occurs around the time of implantation. We think we now have in culture a cell that represents this intermediate stage and that has distinctive functional properties and distinctive molecular properties, said Smith. After capacitation, the formative stem cells undergo a more gradual shift to become primed stem cells, which are the epiblast stem cells in mice.

Smith concedes that the human data are less detailed, but all of the experiments his team was able to do produced results consistent with the mouse model. Other work has also found corroborating results in non-human primate embryos, implying that the same developmental mechanisms are conserved across mammals.

After the presentations, a panel consisting of members of the Innovators in Science Awards Scientific Advisory Council and Jury took the stage to address a series of questions from the audience.

The panel first took up the question of how researchers can better study human stem cells, given the ethical challenges of working with embryos. Brigid Hogan described organoid cultures, in which researchers stimulate human iPS cells to grow into minuscule organ-like structures. This is a way of looking at human development at a stage when its [otherwise] completely inaccessible, said Hogan. Other speakers concurred, adding that implanting human organoids into mice provides an especially useful model.

Another audience member asked about the potential for human stem cell therapy in the brain. Hogan pointed to the use of fetal cells for treating Parkinsons disease as an example, but panelist Hans Schler suggested that that could be a unique case. Patients with Parkinsons disease suffer from deficiency in dopamine-secreting neurons, so implanting cells that secrete dopamine in the correct brain region may provide some relief.

Panelists also addressed the use of stem cells in regenerative medicine, where researchers are targeting the nexus of aging, nutrition, and brain health. Emmanuelle Passegu explained that the bodys progressive failure to regenerate itself from its own stem cells is a hallmark of aging. I think we are getting to an era where transplantation or engraftment [of cells] will not be the answer, it will really be trying to reawaken the normal properties of the [patients own] stem cells, said Passegu.

As the meeting concluded, speakers and attendees seemed to agree that the field of stem cell research, like the cells themselves, is now poised to develop in a wide range of promising directions.

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The New Transformers: Innovators in Regenerative Medicine - NYAS - The New York Academy of Sciences

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A single subretinal dose of a gene therapy was not only well tolerated among patients with neovascular age-related macular degeneration (nAMD), but there was sustained expression of the RGX-314 protein for at least 2 years, showing the potential to control exudation. The results of the phase I/IIa dose escalation trial were published in The Lancet.1

Age-related macular degeneration (AMD) causes vision loss that can turn into partial blindness.

Image credit: Syda Productions - stock.adobe.com

RGX-314, also known as ABBV-RGX-314, is an adeno-associated virus serotype 8 vector that provides potential continuous suppression of VEGF-A. nAMD, also called wet AMD, causes faster vision loss than AMD and, while it doesnt cause complete blindness, can cause patients to lose central vision.2

Real-world outcomes of long-term nAMD treatment have been inferior to those seen in clinical trials because of undertreatment or nonadherence with visits for injections. Therefore, there is strong motivation to develop treatments that provide sustained suppression of VEGF-A, the authors explained.

The open-label, multiple-cohort, multicenter, phase I/IIa, dose-escalation study was conducted at 8 sites in the US with 68 patients. On day 1, all patients received intravitreal ranibizumab. At week 2, 42 who demonstrated the required anatomic response received a subretinal injection of RGX-314. There were 5 different doses being evaluated with 12 patients placed into each cohort based on dosing. The mean (IQR) age at baseline was 80 years (74-85), nearly all (41 of 42) patients were White, and 52% were female.

While all patients experienced at least 1 treatment-emergent adverse event (TEAE), most were grade 1 or 2. The most common TEAEs were postprocedure conjunctival hemorrhage and retinal pigmentary changes. There were also 7 instances of a retinal degeneration event, which were mostly grade 1, typically occurred 6 to 12 months after the gene therapy was administered, and had not resolved at the end of the study.

In 9 of 46 study eyes, reduced visual acuity was reported, although 6 of these were mild or moderate and deemed unrelated to RGX-314. However, the other 3 events were possibly related to the therapy.

The mean baseline best-corrected visual acuity (BCVA) was maintained or improved in 4 of the 5 cohorts, while cohort 1, which received 3x109 genome copies per eye, experienced a gradual reduction in BCVA over time. Patients in cohorts 3 through 5 who did not receive any supplemental antiVEGF-A injections throughout the last year of the study maintained or improved baseline BCVA.

"The publication of the ABBV-RGX-314 Phase I/IIa trial results in The Lancet reinforces the encouraging long-term clinical data observed using subretinal delivery and underscores the potential of ABBV-RGX-314 gene therapy to offer a new approach to the clinical management of wet AMD," Jeffrey S. Heier, MD, director of the Vitreoretinal Service and director of Retina Research at Ophthalmic Consultants of Boston, and primary investigator for the trial, said in a statement.3 "Wet AMD is a chronic, life-long disease and real-world evidence shows patients are losing significant vision over time, and the burden of frequent anti-VEGF injections needed to manage their wet AMD is a major reason why. A single treatment of ABBV-RGX-314 that can potentially provide long-lasting treatment outcomes and a strong safety profile would offer a novel approach to treating this serious and blinding disease."

In an interview4 ahead of the Angiogenesis, Exudation, and Degeneration 2023 meeting, Charles C. Wykoff, MD, PhD, director of research at Retina Consultants of Texas; chair of research, Retina Consultants of America; and deputy chair of ophthalmology for the Blanton Eye Institute, Houston Methodist Hospital; and coauthor on the study, explained that a gene therapy for the most common cause of irreversible blindness would be a tremendous step forward for the opportunity for management of this chronic disease.

He also noted that while gene therapy holds the promise of being one and done, data have shown that some patients do need ongoing therapy.5

"Even if we are using gene therapy, it's important to realize that these patients will continue to need retinal care and retinal follow-up," he said. "You're looking for signs of efficacy, you're monitoring them for safety, you're making sure that they get any retreatments if they need them. Of course, there's a host of other retinal issues that may come up in these patients. They're going to continue to need retina care, certainly, even in the context of gene therapy."

Reference

1. Campochiaro PA, Avery R, Brown DM, et al. Gene therapy for neovascular age-related macular degeneration by subretinal delivery of RGX-314: a phase 1/2a dose-escalation study. Lancet. 2024:S0140-6736(24)00310-6. doi:10.1016/S0140-6736(24)00310-6

2. Age-related macular degeneration. National Eye Institute. June 22, 2021. Accessed April 12, 2024. https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/age-related-macular-degeneration

3. REGENXBIO announces Lancet publication of phase I/IIa study evaluating ABBV-RGX-314 as a one-time gene therapy for wet AMD. REGENXBIO. News release. March 28, 2024. Accessed April 12, 2024. https://regenxbio.gcs-web.com/news-releases/news-release-details/regenxbio-announces-lancet-publication-phase-iiia-study

4. Joszt L. Dr Charles Wykoff: gene therapy for wet AMD would be a tremendous opportunity. The American Journal of Managed Care. May 21, 2023. Accessed April 12, 2024. https://www.ajmc.com/view/dr-charles-wykoff-gene-therapy-for-wet-amd-would-be-a-tremendous-opportunity

5. Joszt L. Dr Charles Wykoff discusses gene therapy to treat wet age-related macular degeneration. The American Journal of Managed Care. April 23, 2023. Accessed April 12, 2024. https://www.ajmc.com/view/dr-charles-wykoff-discusses-gene-therapy-to-treat-wet-age-related-macular-degeneration

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Gene Therapy Well Tolerated in Wet AMD, Shows Promise in Visual Acuity - AJMC.com Managed Markets Network

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You can add Nov. 16, 2023, to July 16, 1945 the day nuclear power moved from the theoretical to the actual as an entry to the list of consequential moments for everyones favorite vertebrate, Homo sapiens.

The news was easy to miss, but there it was. The United Kingdom announced that it would be the first country in the world to approve the use of gene editing as a medical therapy, starting with two inherited types of anemia: beta-thalassemia, and the more widely known sickle cell anemia. The U.S. Food and Drug Administration (FDA) followed suit three weeks later.

Its official: we humans are going to mess with our DNA, our original blueprints. DNA is the genetic instructions dictating how we look and behave, and that define what diseases we may develop, be prone to or be free of. With our ever-improving gene-editing skills, we are now prepared to peel back the pages of this ancient and sacred text and write the story the way we want to hear it.

DNA makes up the letters of lifes instruction manual for humans or any living thing. Genes organize those letters into words and paragraphs. Chromosomes organize those genes into chapters. In humans, each cell has 23 pairs of chromosomes. Inside the cell, DNA provides the formula for manufacturing specific proteins. Its the blueprint that tells each cell what to build, and how to build it.

Unfortunately, DNA can get altered or damaged, an occurrence thats referred to as a mutation. A mutation can be either inherited or newly acquired. It can cause the gene to produce a faulty product or no product at all. In the case of sickle cell disease, a mutation in the gene that codes for hemoglobin a complex protein that allows red blood cells to shuttle oxygen from the lungs to the body can lead to a whole lot of pain and suffering.

Red blood cells are flexible, allowing them to scooch through tiny capillaries where they unload their oxygen. In sickle cell disease, the mutation in the hemoglobin molecule can cause a red blood cell to change shape from a circle to a sickle. Sickled red blood cells lack flexibility, so they plug up the very capillaries they were supposed to be sliding through. Just as a traffic accident can lead to a pileup of cars behind it, one stuck sickled cell can trigger an upstream backup of stuck sickled cells.

Traffic jams are a pain, but a sickle cell attack aptly termed a crisis produces a deep, aching pain that may be unrivaled in human suffering. As capillaries and small arteries plug up, downstream tissues are left without oxygen. These blood-starved tissues begin screaming for oxygen as if their lives depended on it which they do.

Although a sickle cell crisis can cause excruciating pain, thankfully it is only rarely lethal. With pain medications, intravenous fluids, blood transfusions and oxygen support, the pain eventually eases. But repeated episodes take their toll on the body, significantly shortening the life expectancy of those with the disease.

Those with sickle cell disease (SCD) carry two copies of a sickling-prone hemoglobin gene (HbS). One copy comes from each parent. Those with sickle cell trait (SCT) have just one copy of HbS, but thats not enough to cause sickling except in rare circumstances like scuba diving or mountain climbing.

The sickle cell gene seems to have originated in sub-Saharan Africa, where having a single copy of the gene having SCT protects against severe malaria infections. Thats because the parasite that causes malaria, which reproduces by infecting red blood cells, has a harder time doing that inside cells carrying a lone sickle gene.

Although the prevalence of the sickle cell gene remains highest in sub-Saharan Africa, slavery and migration patterns have expanded its global range, so that today SCD can affect people of Hispanic, Southern European, Middle Eastern or Asian Indian backgrounds.

In the United States, 7% to 8% of Black newborns carry the sickle cell trait. In addition, 0.7% of Hispanic newborns, 0.3% of white newborns, and 0.2% of Asian or Pacific Islander newborns carry the trait. One out of every 365 Black newborns will have SCD. In total, about 100,000 people in the U.S. and 20 million people worldwide have SCD. Thats a lot of people hoping for a cure.

Casgevy is the first FDA-approved therapy to use CRISPR gene-editing technology. CRISPR is an acronym we can all be grateful for because it eliminates a phrase we will never be able to remember: clustered regularly interspaced short palindromic repeats.

In the case of Casgevy, CRISPR is used to create a line of red blood cells that manufacture hemoglobin F (HbF) thats F as in fetus. HbF has stronger oxygen-binding characteristics than adult hemoglobin (HbA). Thats because in the womb humans are breathing through the mothers placenta, and not through the lungs, which are filled with amniotic fluid. HbF production typically gets turned off soon after birth. Thats unfortunate for those with sickle cell disease who carry HbS, not HbA because HbF helps prevent sickling.

Casgevy turns HbF production back on.

Lyfgenia works by giving people with sickle cell disease a line of blood cells that can manufacture a form of adult hemoglobin (HbA).

Neither Casgevy nor Lyfgenia completely eliminates sickle cells, but they dilute the concentration of sickle-prone cells, thereby preventing sickle cell crises.

No surprise treatment with Casgevy and Lyfgenia is more complicated than what I just described. It requires removing stem cells from the blood. Stem cells are a little like the queen bee in a hive: They produce all the cells that will keep the body vigorous and healthy. In this application, the stem cells of interest are the ones that manufacture the new red blood cells needed to replace those at the end of their 120-day life span (or 20 to 30 days for fragile sickle cells). After these blood stem cells are removed and sent to the lab for gene therapy, the patient is given chemotherapy to decrease the number of stem cells making sickled red blood cells. This makes room for the new-and-improved stem cells.

Chemotherapy comes in a variety of potencies, and in this case, its fairly potent the kind you need to be in the hospital for. Following the gene therapy infusion, itll be 3 to 6 more weeks in the hospital waiting for the body to recover from the chemotherapy and for the modified stem cells to start growing back in serious numbers.

Like nuclear power or artificial intelligence, the technology of gene therapy brings great promise but also serious risks and ethical concerns.

There are the risks of the treatment itself: Did the gene therapy get inserted into the right gene location, and is it functioning correctly? Or did it end up in the wrong spot, altering the function of genes that we meant to leave alone?

There is the ethical question of who will get stem cell therapy. The medical complexity and steep cost of stem cell therapy a cool $2.2 million for a Casgevy treatment, and $3.1 million for Lyfgenia make it a boutique item only the haves will be able to afford.

And there are the ethics of how and where we will apply the technology. Although history teaches us that H. sapiens is an inventive and curious creature, we also are a never-quite-satisfied, boundary-pushing and occasionally nefarious lot. While were using gene therapy to eliminate sickle cell disease or perhaps someday Alzheimers, cardiovascular disease or what have you someone is going to ask: Whats the harm in getting rid of things like nearsightedness, balding, belly fat, wrinkles? And while were at it, why not use gene therapy to make sure we or our offspring have what it takes to compete in the NBA or the Ivy League, Hollywood or the Navy Seals? And can we eliminate dying?

Dont think we humans will go there? Comedian and futurist Jon Stewart told Stephen Colbert he sees it going this way: The world ends. The last words man utters are somewhere in a lab. A guy goes, Huh-huh. It worked!

Scientists disagree on whether Stewart was joking but recommend further research.

Relevant reading

When Winter Came

Dr. Pierre Sartor wrote an inspiring first-person account of how he treated more than 1,000 patients and by his reckoning, lost only five which lay forgotten in a lockbox of family artifacts until it was discovered decades later by his granddaughter, Beth Obermeyer, a journalist and author of

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Messing with the blueprints: Gene therapy has arrived - Mayo Clinic Press

Recommendation and review posted by Bethany Smith

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Long-Term Ovarian Function Assessment After Haematopoietic Stem Cell Transplantation in Female Sickle Cell ... - Cureus

Recommendation and review posted by Bethany Smith

Induction therapy followed by autologous stem cell transplantation (ASCT) is standard of care for young and fit patients with newly diagnosed multiple myeloma (MM) [1]. Induction therapy has evolved from doublet to triplet to quadruplet regimens over the last decades. The most common triplet therapy is either Bortezomib-Cyclophosphamide-Dexamethasone (VCD), Bortezomib-Lenalidomide-Dexamethasone (VRD), or less frequently Bortezomib-Thalidomide-Dexamethasone (VTD). No large, randomized phase III study comparing the VCD and VRD regimens has been conducted and is unlikely to be done in the future. Retrospective studies and smaller prospective studies comparing VRD and VCD have produced mixed results [2,3,4,5,6,7].

In Norway, there has been a shift from VCD to VRD induction therapy in recent years, while VTD has only been used in a minority of patients. ASCT for multiple myeloma in Norway is performed at four centers, and comprehensive population-based nationwide follow-up data are available from electronic journals.

In collaboration with all centers in Norway doing ASCT, we identified all patients in Norway who had undergone ASCT for multiple myeloma in the study period 2008 to 2020.

We included patients with multiple myeloma [8] who received first line induction therapy followed by ASCT in the period from January 1st 2008 to December 31st 2020 in Norway. We did not include patients who received induction therapy but did not proceed to ASCT. Patients were censored March 1st 2022 or at loss to follow-up because of relocation outside of Norway (n=5), or if the journal from the local hospital could not be obtained (n=7).

Data was collected from electronic patient journals at the transplant centers and from hospitals responsible for induction therapy and follow-up after ASCT. Change of induction therapy was recorded if a patient changed from one line to another, and the reason for change was collected. Patients who changed therapy were not included in the primary response analysis, regardless of the reason for change, but they were included in a separate intention-to-treat analysis. All patients, including those who changed treatment, were included in the PFS and OS analysis. Further description of study design, endpoints and statistical analysis is provided in the supplementary material.

We identified 1354 patients who received ASCT as first-line treatment for multiple myeloma in Norway in the study period.

Of these, 682 patients received VCD induction, 332 patients received VRD induction, and 42 patients received VTD induction. Baseline characteristics are described in Table 1 and were largely similar between patients who received VCD and VRD induction, with two notable exceptions. Patients in the VRD group were older than patients in the VCD group (median 62 years vs. 60 years). Patients in the VRD group received ASCT in more recent years (mostly 2017-2020), compared to VCD.

Three months after ASCT, response rates were higher with VRD, with 89% in the VRD group achieving VGPR, versus 76% in the VCD group (p<0.001). In the intention-to-treat analysis, the difference in response between the groups remained statistically significant (Table 1).

In the VCD group, 4% of patients changed therapy due to lack of response, and 1% due to progression. In the VRD group, very few patients changed treatment due to lack of response (1%) or progression (1%). Only a small minority, 3% and 2% of patients in the VRD and VCD group respectively, changed treatment due to adverse effects (Table 1). In patients who received bortezomib, thalidomide and dexamethasone (VTD), 36% of patients changed treatment due to side effects (Supplementary Table 5).

Patients in the VRD group more often received treatment after ASCT than in the VCD group (61% vs. 14%, p<0.001). Consolidation treatment (22% vs. 1%), maintenance treatment (25% vs. 10%) or both (14% vs. 3%) were all more frequent in the VRD group (Table 1). In the VCD group, 4.7% of patients (n=32) and in the VRD group 3.9% of patients (n=13) had progressive disease before starting consolidation or maintenance treatment.

The median follow-up time of patients still alive at data cut-off was 79 months (range: 19179 months) in the VCD group and 38 months (range: 1871 months) in the VRD group.

In the VCD group, the median PFS was 30.1 months (95% confidence interval (CI) 28.331.9 months). In the VRD group, the median PFS was 55.1 months (95% CI 46.0-not reached (NR), Fig. 1A). The difference was significant on log-rank test, p<0.001. In the VTD group median PFS was 36.6 months (Supplementary Fig. 2)

A PFS, all patients. B PFS, only patients who received maintenance treatment. C PFS, only patients who revied ASCT in later years (20172020) and did not received any post-ASCT treatment. D OS, all patients.

When we included only patients who received maintenance therapy after ASCT, the median PFS in the VCD group increased to 47.1 months, which is not statistically different from patients in the VRD group who received maintenance, who had a median PFS of 56.4 months, p=0.174 (Fig. 1B).

In a separate analysis excluding patients who received maintenance and/or consolidation and who received ASCT in later years (20172020), VRD was superior to VCD regarding PFS with a log-rank test of p<0.001 (Fig. 1C).

The median OS for VCD was 114.0 months (95% CI 103.4125.8 months) and the median OS for VRD was not reached, log-rank test p<0.001 (Fig. 1D).

The hazard ratios for PFS and OS on multivariate analysis is provided in Supplementary Table 2. After controlling for patient and disease factors, VCD had inferior PFS compared to VRD (HR 2.08, 95% CI 1.492.91, p<0.001). There was no significant difference in OS between the two regimens in multivariate analysis.

VTD is approved by the European Medical Agency as induction therapy before ASCT. This is not the case for VCD and VRD, although they are used widely in current clinical practice. The most recent European Society of Medical Oncology (ESMO) guidelines [1] recommend VRD as the first option for induction therapy. Daratumumab-VTD is also approved and recommended, but our study confirms the high toxicity associated with regimens containing thalidomide. VRD is the comparator arm in recent clinical trials comparing Daratumumab-VRD vs VRD before ASCT [9, 10]. Our study supports the use of VRD in both clinical practice, and as the standard treatment arm in clinical trials, as it is more effective than VCD and better tolerated than VTD. However, recent results from the PERSEUS trial [9], with significantly longer PFS for Daratumumab-VRD vs VRD, will most likely be practice changing.

We observed a statistically significant improvement in both PFS and OS favoring VRD. This must, however, be interpreted with caution. The difference in use of post-ASCT therapy, and the time periods in which the regimes were given, are two major biases. We corrected for this by performing a separate analysis for only patients who received ASCT in later years and who did not receive consolidation and/or maintenance therapy. In this analysis VRD still showed significantly longer PFS compared to VCD. The median PFS was also longer in the VRD group when only patients who received maintenance therapy were included, although the difference was not statistically significant. Multivariate analysis showed a statistically significant PFS benefit favoring VRD, but no statistically significant OS benefit. Given the median overall survival in our data of approximately 9.5 years in the VCD group, induction therapy administered for 24 months represents only a fraction of this total observed time. Therefore, the effect of induction therapy on overall survival may be modest, and other factors, like treatment options available at relapse, will have a significant impact on patient survival. Most patients in the VCD group received ASCT before 2017, when consolidation and maintenance treatment were uncommon and fewer treatment options were available at relapse, affecting the survival of this group negatively. Conversely, in the VRD group, most patients received ASCT after 2017. In this period, maintenance treatment was usually given (or consolidation treatment when maintenance was not reimbursed), and effective treatments like CD38-antibodies and carfilzomib were available at relapse.

The main limitation of the study is its retrospective nature, and as patients were not randomized, confounding factors cannot be excluded. However, the type of induction the patient received was mainly dependent on center and not on patient or disease factors. Standard induction therapy differed between regions, where some centers consistently used VCD while others consistently used VRD. In Norway, access to new therapies is similar for all, and national and regional treatment guidelines are usually the factors that determine choice of treatment, and to a lesser degree individual patient risk factors. Furthermore, a limitation was that we only included patients who received ASCT. Patients who died before ASCT, started induction therapy but for various reasons did not proceed to ASCT, including those who could not harvest enough stem cells, were not included. The follow-up time for VRD patients was relatively short. Patients were included from many different hospitals in Norway over a long period of time, with variable practices regarding timing of treatment start, dosing schedules, response assessment and supportive care. Although the data quality was generally good, some data was missing and incomplete.

Our study is the first to report from a comprehensive nationwide, population-based cohort with a very low proportion of patients lost to follow-up. This is a major strength, as the inclusion of a broad, heterogenous population increases the generalizability of the results and reduces the risk of selection bias. Our data included an overlap period where both regimens were given. Apart from the type of induction therapy, the treatment course between the two groups were similar; Length of induction treatment, the ASCT procedure and time to response evaluation was unchanged throughout the study period and similar for both groups.

In conclusion, our results suggests that VRD should be preferred to VCD as induction therapy for newly diagnosed MM patients who are eligible for ASCT.

Original post:
VRD versus VCD as induction therapy before autologous stem cell transplantation in multiple myeloma: a nationwide ... - Nature.com

Recommendation and review posted by Bethany Smith

In recent years, the field of regenerative medicine has witnessed remarkable advancements in the use of dental stem cells. The discovery of these tiny but potent cells nestled within our teeth has sparked excitement among researchers and medical professionals alike, offering new avenues for treating a myriad of diseases and injuries.

A journey through stem cell history

Stem cells are cells that have the unique ability to develop into various specialized cell types in the body. This capacity for differentiation is what makes them invaluable in regenerative medicine.

The history of stem cell research traces back to the mid-twentieth century. In the 1960s, Canadian scientists James Till and Ernest McCulloch conducted experiments demonstrating the existence of stem cells in bone marrow, the spongy tissue inside bones that can produce blood cells, after introducing new cells into the bone marrow of irradiated mice. This work laid the foundation for further exploration into the therapeutic potential of stem cells.

Since then, researchers have identified stem cells in various tissues throughout the body, including in dental pulp, the soft tissue inside teeth. Dental stem cells have garnered particular interest due to their easy accessibility and regenerative capabilities.

Within the dental pulp, researchers have identified several types of stem cells, each with its own unique properties and potential applications.

Dental pulp stem cells

Dental pulp stem cells (DPSCs) are stem cells found in the centre of teeth. They have unique abilities to grow and transform into different types of cells, like those found in teeth, nerves, bones, muscles, and even certain organs. These cells can help in repairing damaged teeth and treating various diseases.

DPSCs are isolated from dental pulp tissue, typically obtained from third molars, also known as wisdom teeth, that are often extracted and discarded. The isolation process does not involve invasive surgical procedures and poses no harm to the donor.

DPSCs have the ability to repair damaged or diseased dental tissues. They can become tooth-building cells called odontoblasts cells that form dentin, the hard tissue beneath the enamel and osteoblasts cells that build jaw bone. This could revolutionize dental treatments by enabling the regeneration of natural tooth structures, reducing the need for fillings, crowns, and other restorative procedures.

DPSCs may even be able to help treat several medical conditions. In nerve-related conditions, such as nerve trauma or neurodegenerative diseases, patients may experience a loss or damage of neurons that need replacement or repair. DPSCs can help as they possess the ability to differentiate into neuron-like cells. Surprisingly, they can also secrete neurotrophic factors, which are biomolecules that support the growth, survival, and function of neurons and promote neuronal repair.

In conditions where the immune system is overactive such as inflammatory or autoimmune diseases, or neuroinflammation in neurodegenerative diseases such as Parkinsons disease DPSCs can help calm down the immune system by releasing molecules that reduce viral replication and reduce inflammation produced by the immune system.

Additionally, DPSCs have also shown promise in repairing damaged heart tissue and improving blood flow in conditions like heart attacks and leg artery blockages, including by stimulating formation and repair of blood vessels.

Stem cells from human exfoliated deciduous teeth

In 2003, researchers discovered a variety of stem cells in shed baby teeth, which are scientifically known as human exfoliated deciduous teeth. These cells have the remarkable ability to transform into various cell types like bone, nerve, and liver cells and can specialize into other types of stem cells.

When transplanted into living organisms, stem cells from human exfoliated deciduous teeth (SHEDs) show potential in repairing bone defects and forming new dental tissue.

SHEDs also possess immune-regulating properties according to studies in mice, and they could be beneficial for treating diseases like lupus by balancing the immune response. This means that we may be able to treat lupus, which is a genetic disorder characterized by the inflammation of different tissues, with stem cells used to repair damaged nerves and slow progression. This treatments success is proportional to a patients age and duration of condition.

Immature dental pulp stem cells

In recent studies, researchers have identified a special type of dental stem cells known as Immature Dental Pulp Stem Cells (IDPSC), also found in the dental pulp of baby teeth. These cells express certain markers that indicate they are at an early stage of development and are markers in embryonic stem cells.

One exciting discovery is that when researchers transplanted cell sheets made from undifferentiated IDPSC into rabbits with damaged corneas the outermost layer of the eye they observed the regeneration of the outer layer of the cornea. This finding suggests potential applications in treating corneal injuries and reconstruction.

Moreover, experiments involving the transplantation of IDPSC into immunocompromised mice and dogs have demonstrated promising results. The transplanted IDPSC were able to integrate well into various tissues and significantly improve conditions such as muscular dystrophy in dogs, without triggering immune rejection.

Harnessing the healing power of dental stem cells

The versatility of dental stem cells holds immense promise for regenerative medicine. Researchers are exploring a wide range of potential applications, including dental regeneration, bone regeneration, and neurological disorders.

As research continues to advance, we may soon see these tiny but mighty cells transform the landscape of healthcare, offering new hope for patients suffering from a wide range of conditions. From repairing damaged teeth to restoring neurological function, the possibilities seem to be truly endless.

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Unlocking the healing potential of dental stem cells - Varsity

Recommendation and review posted by Bethany Smith

A long-awaited final report on the state of treatment for gender dysphoria in children and teens under the care of Englands National Health Service (NHS) has revealed the current clinical approach utilizing puberty blockers and cross-sex hormones is based on remarkably weak evidence stemming from poor quality of the published studies, and misinformation while exhibiting expectations of care that are far from usual clinical practice.

In the foreword to the report, British pediatrician Dr. Hilary Cass, who led an independent review team from the University of York, wrote that while the medical field is usually cautious in recommending new treatments for children and teens, quite the reverse happened in the field of gender care for children:

This is an area of remarkably weak evidence, and yet results of studies are exaggerated or misrepresented by people on all sides of the debate to support their viewpoint. The reality is that we have no good evidence on the long-term outcomes of interventions to manage gender-related distress.

[T]he toxicity of the debate is exceptional, Cass said about the issue of medical gender treatments for children. The knowledge and expertise of experienced clinicians who have reached different conclusions about the best approach to care are sometimes dismissed and invalidated.

The reports summary clearly asserts that, while some think the clinical approach should be based on a social justice model, the NHS works in an evidence-based way.

Our current understanding of the long-term health impacts of hormone interventions is limited, the review notes as it also acknowledges the rapid surge in referrals for such medical treatment.

The numbers of children and young people presenting to the UK NHS Gender Identity Service (GIDS) has been increasing year on year since 2009, with an exponential rise in 2014, the report observes, noting the use of puberty blockers began following the emergence of the Dutch Protocol.

The review team stressed the rapid push to utilize puberty blockers, despite any evidence showing effectiveness:

Preliminary results from the early intervention study in 2015-2016 did not demonstrate benefit. The results of the study were not formally published until 2020, at which time it showed there was a lack of any positive measurable outcomes. Despite this, from 2014 puberty blockers moved from a research-only protocol to being available in routine clinical practice and were given to a broader group of patients who would not have met the inclusion criteria of the original protocol.

The systematic review by the University of York found multiple studies that show puberty blockers not only suppress puberty, but also compromise bone density.

Yet, evidence regarding the use of puberty blockers and cross-sex hormones to treat gender dysphoria had already been shown to be weak, with a lot of misinformation easily accessible online and remaining currently, the review stated.

The World Professional Association of Transgender Healthcare (WPATH) has been highly influential in directing international practice, although its guidelines were found by the University of York appraisal process to lack developmental rigour, the report asserts.

In March, leaked internal files from WPATH, often touted by Dr. Rachel (born Richard) Levine, a top Biden HHS official, as the premier organization for evidence-based treatment recommendations, revealed its doctors acknowledging children and teens were not capable of comprehending the possible long-term effects of the treatments and surgeries they were prescribed.

The review team notes that while research suggests gender expression is influenced by biological predisposition, early childhood experiences, sexuality and expectations of puberty, and, therefore, requires a multi-disciplinary team approach to assessing the problem areas for each individual child, the most striking problem is the lack of any consensus on the purpose of the assessment process.

Some service users and advocates view an extensive exploration of other conditions and diagnoses as an attempt to find any other reason for the persons distress other than them being trans, the team observes.

While the report states there are some young people for whom medical treatment for gender dysphoria will be the best outcome, it notes as well young adults looking back at their younger selves would often advise slowing down as they and their parents weigh the ramifications.

Some may transition and then de/retransition and/or experience regret, the review acknowledges, concluding a medical pathway is not the best treatment protocol for the majority of young people:

[T]he focus on the use of puberty blockers for managing gender-related distress has overshadowed the possibility that other evidence-based treatments may be more effective. The intent of psychosocial intervention is not to change the persons perception of who they are, but to work with them to explore their concerns and experiences and help alleviate their distress regardless of whether or not the young person subsequently proceeds on a medical pathway.

[N]o changes in gender dysphoria or body satisfaction were demonstrated as a result of puberty blockers, the report plainly asserts.

The review team also addressed the controversy over social transition what has become known as the initial phase of so-called gender-affirming care.

The systematic review showed no clear evidence that social transition in childhood has any positive or negative mental health outcomes, and relatively weak evidence for any effect in adolescence, the report concludes. However, those who had socially transitioned at an earlier age and/or prior to being seen in clinic were more likely to proceed to a medical pathway.

Reviewers similarly found no support for the claim by transgender activists that administering puberty blockers allows time for children and their families to consider further medical intervention:

[G]iven that the vast majority of young people started on puberty blockers proceed from puberty blockers to masculinising/ feminising hormones, there is no evidence that puberty blockers buy time to think, and some concern that they may change the trajectory of psychosexual and gender identity development.

There is a lack of high-quality research assessing the outcomes of hormone interventions in adolescents with gender dysphoria/incongruence, and few studies that undertake long-term follow-up, the review team explains.

In addition, reviewers found no evidence to support the transition or die claim that hormone treatment prevents a high risk of suicide in minors with gender dysphoria.

>> FINNISH STUDY: GENDER-AFFIRMING CARE DOES NOT REDUCE YOUTH SUICIDE <<

The primary predictor of death in gender-dysphoric young people is psychiatric morbidity, the researchers said. Medical gender reassignment does not have an impact on suicide risk.

The current evidence base suggests that children who present with gender incongruence at a young age are most likely to desist before puberty, although for a small number the incongruence will persist, the Cass report concludes.

This final report stresses the need for a holistic assessment of children and teens referred for gender services:

This should include screening for neurodevelopmental conditions, including autism spectrum disorder, and a mental health assessment.

Standard evidence based psychological and psychopharmacological treatment approaches should be used to support the management of the associated distress and cooccurring conditions, the team recommends. This should include support for parents/carers and siblings as appropriate.

The release of the Cass report comes only days after Dignitas Infinita on Human Dignity, the most recent document from the Dicastery for the Doctrine of the Faith (DDF), was issued.

The DDF declaration addresses human dignity and reaffirms traditional teachings of the Church, including those on gender ideology and sex-change surgery.

>> READ CVS ANALYSIS OF DIGNITAS INFINITA HERE <<

More:
Report Cites 'Misinformation,' 'Remarkably Weak' Evidence to Support Use of Puberty Blockers and Cross-Sex ... - CatholicVote org

Recommendation and review posted by Bethany Smith

What the public may not be aware of, is that it is relatively common for treatments to be offered in health and mental health, where the research evidence is still emerging and/or limited"

Dr Paul Skirrow, clinical psychologist and neuropsychologist, and strategic advisor at the New Zealand College of Clinical Psychologists, comments:

"We would urge the public to interpret the findings of these reviews with some caution - many people will assume that this research suggests that puberty blockers and hormone treatments should never be offered, which would be mistaken.

The authors ultimately conclude that: No conclusions can be drawn [about the effect of puberty blockers]. This research highlights that we currently do not know how effective these treatments are, or who they are most effective with, but there are many reports of benefit from the people who use them and clinicians who provide them. What research we do have, albeit of limited quality at present, appears to suggest there may be benefits overall, however, we do not currently know who specifically is likely to benefit.

With regard to hormone treatments, the authors do conclude that There is suggestive evidence from mainly pre-post studies that hormone treatment may improve psychological health. However, again, they clearly state that robust research with long-term follow-up is needed.

What the public may not be aware of, is that it is relatively common for treatments to be offered in health and mental health, where the research evidence is still emerging and/or limited. The choice for clinicians is frequently whether to offer nothing - which is unlikely to be helpful - or offer something that we agree can be helpful for some people.

"In doing so, we recommend that the person undergoing these treatments gets the best possible information on what we know about their risks and benefits. For this reason, we very much welcome research studies, such as those released today, which help us fully understand what they may be."

Conflicts of interest statement: I'm not aware of any potential conflicts of interest. My role with the NZCCP involves speaking on behalf of the organisation, specifically the executive leadership team. We have approximately 1800 members, who hold a wide range of views, and so my comments may or may not reflect those of individual members. I also hold a senior lecturer position at Otago University, specialising in neuropsychology.

Link:
Review of evidence for puberty blockers and hormone treatment in youth - New Zealand Doctor Online

Recommendation and review posted by Bethany Smith

Sponsored by Embark

Adam Christman, DVM, MBA: We talk a lot now about spectrum of care. What happens to the dog parents, unfortunately, who cannot afford the price of DNA testing? We really want to recommend it, but they just dont have the funds. What are your thoughts on that?

Jenna Dockweiler, MS, DVM, DACT, CCRT, CVAT: DNA testing is fairly cost effective and it will only become more so in the future. A dog's DNA is the same from the day it's born to the last day of that pet's life. So really at any point along that journey, it is appropriate to DNA test. Potentially in the future, as costs come down with just the testing technology itself, it will likely become more accessible for those folks.

Adam Christman, DVM, MBA: What about the practice that says, "We don't have the time for this?

Lindsey Kock, DVM: I think it's one of those things that taking the time to do that DNA test enables you to have more time later. By taking the time to do that test, you no longer have a full laundry list of things to cover at that puppy exam, but you have a few individual talking points.

We talked about compliance, but if you have the genetic testing to back up the recommendations, you're spending less time teaching and helping the pet parent to understand those things that come up. Something that really is a pretty quick, minimally invasive test, the results can be a lot, but Embarks done a great job of whittling down those results. You take that and you save yourself time in the long run. So it's a little effort for, I think, a huge increased efficiency and increased payoff in the long run.

Adam Christman, DVM, MBA: Okay, are there specific dog breeds that, I don't want to say they have predispositions, but need DNA testing more than other dog breeds out there?

Jenna Dockweiler, MS, DVM, DACT, CCRT, CVAT: We all know there are certain breeds predisposed to certain genetic conditions. I think that's a known truth at this point in veterinary medicine, but certainly testing is appropriate for every dog at every age. Even conditions that we see or think of as particularly breed-associated may not be as breed-associated as we thought, which the urate stones would be a great example of something like that.

And the dog's DNA is going to be the same from when it's born to the last day of that pet's life. So you can test it anytime during that spectrum. And some of these diseases won't manifest until later in life.

Adam Christman, DVM, MBA: I want to talk a little bit about taking away some of the financial issues or burdens that can happen. I find, personally, when you DNA test these dogs and puppies that are coming in, that the clients are more likely to say, oh, let me get pet insurance, just to help take away some of that financial stress that can happen down the road. Have you experienced that in your neck of the woods?

Lindsey Kock, DVM: Yeah, it'll be interesting to see how genetic results have an impact on health insurance. I think today, genetic results are really giving us more insight into potential issues down the road, right? And I think a lot of insurance coverage to my knowledge is based on actual diagnosed conditions that we're seeing clinical signs for, but using some caution too in that and potentially getting the insurance on board first and then doing the genetic test may not be a bad idea.

But I think too, aside from insurance, just being able to be financially prepared for decisions that you may have to make down the road, right? So we talked about intervertebral disc disease (IVDD) with those at an increased risk. Dogs who have at least one of those mutations tend to be at like 45 fold more increased risk of having an episode, but also out of five to 15 increased risk for needing surgery, right? So being able to prepare early for that financial burden and being able to be prepared for that decision, whether you're saving up or you have insurance is really important.

Adam Christman, DVM, MBA: I know we chatted a few years ago about this and I'll share the story with all of you out here because some of you, probably all of you, know I'm a huge dashchund fan. I did want to do the DNA testing for Clark W. Griswald and Lindsay was the one to say you really should, just so that way you know if there's the marker. Well, lo and behold, he did, and this past summer he did have inner vertebral disc disease. He did fantastic, but I expected it. I had pet insurance for him. Granted, I'm his veterinarian, but I can't do the surgery, but it made me so much more aware as a dog dad, knowing like, okay, I know what's gonna happen as much as I had dog ramps, and anything that you try to do. I didn't have that huge panic feeling especially with IVDD when the dogs go down.

Lindsey Kock, DVM: It is hard. Yes, like I don't care who you are. Getting a dog to keep quiet is hard.

Adam Christman, DVM, MBA: I remember talking to clients in the exam room about this with IVDD just because it could be so scary to see your dog walking all of a sudden just go down. But I tell them to be prepared, just like you were talking about, just to know what to expect in case. And I have noticed in my experience that these clients, they're more responsible with the decision-making. Yes, they're emotional, but not nearly as emotional because we already had that discussion. Have you heard that too exactly?

Jenna Dockweiler, MS, DVM, DACT, CCRT, CVAT: Exactly. It's a more proactive discussion, like we were talking about earlier, rather than reactive. So you can tell this client, hey, this is what you're gonna look out for. Maybe they're gonna be wobbly in their hind end, have some back pain, or maybe, go all the way down. They're not panicked about what could this be. It's already, I have a good idea of what this might be and I know I need to seek veterinary attention.

Adam Christman, DVM, MBA: Yes, absolutely.

Excerpt from:
Being prepared for the future - DVM 360

Recommendation and review posted by Bethany Smith

(Scott Sommerdorf | The Salt Lake Tribune) Researchers walk in one of the huge research labs at the Huntsman Cancer Institute, Wednesday, August 26, 2015.

By Josh Bonkowsky | For The Salt Lake Tribune

| April 10, 2024, 12:05 p.m.

Why should we get the test?

Cassies mother was not convinced that we should test her daughter for genetic mutations that could cause epilepsy. In class at school, Cassie (whose name Ive changed for privacy) had a generalized tonic-clonic seizure that lasted for 20 minutes. The next week, she started to have smaller seizures several times a day.

I am a pediatric neurologist, and every year we see more than 1,500 children with new epilepsy in our clinics and in our hospital. For Cassie, the important steps to understand and treat her epilepsy were to order an electroencephalogram or an EEG; to get a brain MRI scan and to test for genetic mutations. We started Cassie on lamotrigine, a very effective and safe anti-seizure medicine.

These decisions about how to take care of Cassie result from cumulative learning and the passing on of information from one generation to the next. Sometimes the chain of knowledge gets lost.

Our current knowledge about epilepsy diagnosis and care; and the field of medicine in general; are guided by the scientific method, one of the great triumphs of the Enlightenment, an 18th century intellectual movement that emphasized reason over superstition. The scientific method holds that we can learn facts and make hypotheses about ourselves and our world; and critically, that the hypotheses are testable.

Our newest tool for epilepsy is genetic testing. Several months after her first seizure, we did genetic testing for Cassie and found that she had a mutation in the SCN1A gene. The SCN1A gene works in the neurons of the brain to maintain a normal electrical balance. It turns out that lamotrigine is not a good choice for people who have SCN1A mutations and can worsen seizures over time. We stopped the lamotrigine and started a different medicine (clobazam). The genetic testing was critical for Cassies treatment.

This power to understand and treat diseases like epilepsy is a triumph of our biomedical enterprise; which is an accomplishment of our society, guided by the values of the Enlightenment.

These values are under threat from both commercialism and sciolism.

Commercialism or the belief that financial profit is valued above all else is corrupting our societys ability to provide equitable care. When I meet with families in my clinic, I have to ask what their insurance is, because I know that, for some, it will be difficult or impossible for them to afford the genetic testing or afford the best medicine.

Sciolism or the arrogance of absolute certainty leads to being convinced of something in the absence of actual knowledge. For example: Some of the families I work with are afraid to start an anti-seizure medicine for their child, or to get genetic testing, after reading about risks or misinformation on the internet. Anti-seizure medicines work very well and, as in Cassies case, genetic testing is important. It is a much bigger risk to a child, by a considerable amount, to not be treated or tested. There are, of course, definite limits of knowledge, and the potential for problems even if very rare. But the reality is that physicians and scientists provide true expertise that can prevent disease and save lives.

What we need is a re-Enlightenment.

The re-Enlightenment should incorporate dedication to the scientific method and valuing of the universal rights of a person, aspects missing from the original Enlightenment. People from disadvantaged and overlooked groups must be part of the discourse; and the importance of the spiritual can not be discounted. Policy decisions need to incorporate true equality of opportunity including housing, health care and financial stability for all persons, whether they are a university professor, a school teacher or a janitor.

The accomplishments of the Enlightenment are real, and we can take those best approaches and best values in a re-Enlightenment. We need a shared commitment that agrees upon rationality and a scientific approach for taking care of our children; that values our humanity and all of its members. The stakes are too high and too important to not take this on.

(Photo courtesy of Josh Bonkowsky) Josh Bonkowsky

Josh Bonkowsky, MD, PhD, is a professor of pediatrics at the University of Utah and director of the Center for Personalized Medicine at Primary Childrens Hospital. The views expressed here are his own and do not necessarily reflect those of his employer.

The Salt Lake Tribune is committed to creating a space where Utahns can share ideas, perspectives and solutions that move our state forward. We rely on your insight to do this. Find out how to share your opinion here, and email us at voices@sltrib.com.

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Opinion: Misinformation and profits keep doctors like me from offering Utahns the best care - Salt Lake Tribune

Recommendation and review posted by Bethany Smith

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Excerpt from:
Adeno-associated virus as a delivery vector for gene therapy of human diseases | Signal Transduction and Targeted ... - Nature.com

Recommendation and review posted by Bethany Smith

In a recent review published in Signal Transduction and Targeted Therapy, researchers presented recombinant adeno-associated virus (rAAV)-based genetic applications to treat human diseases.

Study:Adeno-associated virus as a delivery vector for gene therapy of human diseases. Image Credit:Gorodenkoff/Shutterstock.com

Adeno-associated virus (AAV) is a crucial component of clinical gene therapy due to its low pathogenicity and capacity to generate long-term gene expression in various tissues. Recombinant AAV (rAAV) is designed to increase specificity and can cure several illnesses.

However, concerns persist concerning the safety of high-dose viral therapy in people, as well as immune responses and side effects. Researchers prefer AAV vectors due to their broad tissue tropism, high safety profile, and adaptability in manufacturing procedures.

In the present review, researchers explored AAV-vectored genetic treatment of human disorders.

AAV-1, 4, and 7,8 originate from non-human primates (NHP), while AAV-2, 3, 5, 6, and 9 originate from humans. Primary receptors for cellular attachment include N-linked sialic acid, O-linked sialic acid, HSPG, and galactose.

Co-receptors for cellular attachment include fibroblast growth factor receptor 1 (FGFR1), hepatocyte growth factor receptor (HGFR), laminin receptor (LamR), a cluster of differentiation 9 (CD9), tetraspanin, platelet-derived growth factor receptor (PDGFR), and epidermal growth factor receptor (EGFR).

Receptors for post-attachment for AAVs include the adeno-associated virus receptor (AAVR) and G protein-coupled receptor 108 (GPR108).

AAVs localize in the skeletal muscle, central nervous system (CNS), lungs, retina, liver, pancreas, kidney, and heart.

Natural AAV mutants are isolated from non-human primates and humans using high-cycle polymerase chain reaction (PCR) with high-throughput genetic sequencing. Rational design entails altering amino acid molecules in AAV capsids to boost transduction capabilities or elude immune surveillance.

The directed evolution engineering strategy is used to create unique AAV variations with specificity. In silico techniques, known as AAV capsid sequences, they are used to rebuild ancestral sequences of the virus.

Machine learning uses mutagenized AAV-transduced data to predict the link between AAV genome sequences, packing capacities, and site tropism.

Viral infection and transfection platforms are primarily used to manufacture rAAVs. Plasmid temporary transfection of the human embryonic kidney 293 (HEK293) cell lines continues to be the most often used approach; however, stable cellular lines and systems using baculovirus (BV) or herpes simplex virus (HSV) provide scalable options for scalable manufacturing.

TESSA, a transfection-free system of helper viruses, was designed to generate high-yield recombinant AAVs.

All-in-one producer cells that can be induced pharmaceutically might be the best production platform to obtain recombinant AAV-based pharmaceuticals in the future.

Recombinant AAV gene therapy is effective in treating a wide range of human diseases, including ocular (X-linked retinoschisis pigmentosa, choroideremia, Leber hereditary optic neuropathy), neurological (Alzheimers disease, Parkinsons disease, Huntingtons disease), metabolic (glycogen storage disease, mucopolysaccharidosis, Pompe disease, and Fabry disease), hematological (Hemophilia A, B), neuromuscular (Duchenne muscular dystrophy), cardiovascular (ischemic cardiomyopathy, dilated cardiomyopathy, and congestive heart failure), and gastric cancer.

The ocular immune-privileged condition and tiny volume make it ideal for gene therapy, with various delivery options available. FDA-approved rAAV gene treatments for neurological diseases employ stereotactic, physically limited delivery or extensive CNS transduction by intravenous (IV) administration.

In cellular hematologic circumstances, bone marrow stem cells dilute the rAAV genome, releasing acellular components into the circulation. Recombinant AAV has shown promise in preclinical cancer investigations, but its application to individuals is restricted.

Anti-tumor techniques based on rAAV provide advantages such as regulating or inhibiting gene expression.

Delivery routes determine the performance of rAAV capsids, including intravascular, direct intra-tissue injection, and distribution into pre-existing body cavities or fluid spaces. Each route and capsid is selected based on the ailment, target location, organ system, and patient age.

Intravascular injection enables extensive transduction, although large dosages are necessary. The intra-tissue injection is invasive and confined, whereas intra-cavity administration is distributed in an already established space but may be limited. Intra-fluid delivery has drawbacks, including long vector transit distances.

Recombinant AAV administration, including serotypes, promoters, and enhancers, can cause side effects such as genotoxicity, carcinogenesis, liver damage, thrombotic microangiopathy, and microvascular thrombosis.

Intravenous administration can result in hepatotoxicity, increased liver enzymes, and drug-induced liver damage. Intravenous treatment may result in dorsal root ganglion toxicity, immune cell infiltration, and nerve cell body degeneration.

Edema, inflammation, gliosis, and immunological infiltration are observed on brain magnetic resonance imaging (MRI) scans following intrathecal and intraparenchymal rAAV injections.

The review highlights rAAV-based gene therapy applications for human illnesses. Early success in treating monogenic disorders demonstrated its safety and efficacy.

Challenges include effective delivery, overcoming physical constraints, and understanding rAAV immunogenicity. Strategies for regulating immune responses are critical for patient safety.

Understanding rAAV integration aids in predicting tumor growth, hepatotoxicity, neurotoxicity, and adverse consequences. Further research could assess vector immunogenicity, dosage optimization, and long-term safety.

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Adeno-associated virus: The gene therapy revolution faces manufacturing and safety hurdles - News-Medical.Net

Recommendation and review posted by Bethany Smith

According to the latest research by nova one advisor, the global cell and gene therapy market size was valued at USD 18.13 billion in 2023 and is anticipated to reach around USD 97.33 billion by 2033, growing at a CAGR of 18.3% from 2024 to 2033.

Request PDF Sample Copy of Report: (Including Full TOC, List of Tables & Figures, Chart)@ https://www.novaoneadvisor.com/report/sample/7720

The cell and gene therapy market provides therapeutic solutions related to genes and cells. The market deals with research & development, testing, production, and distribution of products and treatment procedures related to genes and cells. Hospitals, research laboratories, pharmaceutical companies, pharmacies, research institutions, and universities are involved in delivering the applications associated with gene and cell therapies. Gene and cell therapies are developed to prevent, treat, or potentially cure numerous diseases. The potential of these therapies to cure, treat, or prevent diseases that are life-threatening increases the demand and boosts the growth of the market. Gene and cell therapies are used in blood stem cell transplantation, gene editing, engineering of the immune system, tissue regeneration, in-vivo gene transfer, cancer treatment, and treatment of different disorders. These therapies can provide better results and enhance quality of life.

North America dominated the cell and gene therapy market in 2023. North America is a developed region that has developed healthcare and research infrastructure, better facilities, and government support that boosts the growth of the market. Governments in the North American region have a huge national budget for healthcare and research. Countries like the U.S. and Canada contribute to the growth of the market in the North American region. As of now, the FDA has approved 37 products for gene and cell therapy. The U.S. has the American Society of Gene & Cell Therapy (ASGCT) for professionals, scientists, physicians, and patient advocates that help advance knowledge, education, and awareness for discovering and developing clinical applications of gene and cell therapy.

The Canadian government is also focusing on improving health with the help of genes and therapies and is launching various programs to help with this. The government launched Disruptive Technology Solutions, which will help tackle the challenges associated with gene and cell therapies. The treatment procedures will be done to cure rare genetic disorders and chronic diseases.

Key Takeaways:

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The cell and gene therapy market is exploding globally

Ground-breaking developments in next-generation cell and gene therapies (CGTs) offer curative value for patients with few to no other therapeutic interventions for either maintenance or cure within specific disease areas, many of which include rare and ultra-rare diseases.The largest therapeutic area is cancer, followed by musculoskeletal diseases and eye diseases.Multiple approved products have been launched in global markets and the number of clinical trials continues to grow. In Europe, these therapies are classified under Advanced Therapeutic Medicinal Products (ATMPs) and are driven by a diverse set of scientific advancements including CAR-T, TCR-T, stem cells, siRNA, oligonucleotides, gene editing (CRISPR, Zinc Fingers, TALENs) and viral transfection.

The global CGT market is projected to grow at a compound annual growth rate of over 36 percent from 2019-2025, to ~ 10 billion. With more than 900 companies globally focusing on CGTS and over 1,000 clinical trials being conducted, the industry could see numerous approvalsas many as 10 to 20 new advanced therapies per year starting in 2025. Moreover, 33% of these clinical trials is being conducted in Europe.1

Global biopharma companies as well as smaller, venture backed-up start-ups are rapidly investing in this complex space. In 2018, about $13 billion has been invested globally in advanced therapies such as cell, gene and gene modifying therapies. In 2019, 19 CGT-related M&A deals worth over $156 billion were completed.

As with any innovative and disruptive technology, CGT developers face challenges along several key stages of the product life cycle. Compared to chemical-based pharmaceuticals, key success factors such as enabling patient access, managing supply chain and manufacturing operations, evidencing compliance with increasingly complex regulatory requirements and alternate business models impose a greater burden.

Segments Insights:

By Therapy Insights

The market for cell and gene treatments consists of companies (organizations, sole proprietors, and partnerships) that sell the therapies they have developed. Cell therapy is the transfer of whole, living cells derived from allogeneic or autologous sources, while gene therapy is the introduction, deletion, or alteration of the genome to treat disease. The market is made up of the money that businesses creating goods for cell and gene therapy make from the sales of those items.

Cell treatment and gene therapy are the two primary product categories in this field. Gene therapy is a field of medicine that focuses on altering cells' genetic make-up to treat disease or reverse it by repairing or replacing genetic material that has been damaged. Oncology, dermatological, musculoskeletal, and other applications are among the many that are used in hospitals, ambulatory surgery centers, cancer treatment facilities, wound care facilities, and other industries.

Cell & Gene Therapy Market Revenue, By Therapy Type, 2022-2032 (USD Million)

By Therapy Type

2022

2023

2027

2031

2032

Cell Therapy

13,396.01

15,621.48

29,433.95

57,138.21

67,757.69

Gene Therapy

2,067.97

2,502.14

5,406.11

11,864.27

14,480.51

By Therapeutic class

Based on application, the market is divided into cardiovascular disease, cancer, genetic disorder, rare diseases, oncology, hematology, ophthalmology, infectious disease, neurological disorders. Among these, the infectious disease segment dominates the market in 2023. The oncological disorder segment held a revenue share of 13.53% in 2023. Research and treatment in the biomedical domains of cell therapy and gene therapy. Both treatments have the ability to lessen the underlying cause of hereditary disorders and acquired diseases. Both therapies aim to treat, prevent, or perhaps cure diseases. By repairing or changing specific cell types, or by employing cells to transport a medication across the body, cell therapy tries to treat diseases. Cell therapy involves growing or modifying cells outside of the body before injecting them into the patient. The cells may come from a donor (allogeneic cells) or the patient (autologous cells)6. By replacing, deactivating, or introducing genes into cells, either inside the body (in vivo) or outside the body, gene therapy seeks to treat disorders (ex vivo).

The market for genetic disorders is expanding as a result of factors like the high prevalence of genetic and chronic disease cases and the growing government initiatives to raise public knowledge of genetic testing and diagnosis. Researchers are developing novel techniques for screening, diagnosing, and treating patients for a variety of cardiac diseases as they investigate the genetic roots of heart and vascular illness. Some researchers are looking for new ways to nine patients who are at risk for sudden cardiac death. Others are examining how medicines that could postpone or obviate the need for cardiac surgery could benefit patients with uncommon illnesses.

The intricacy of mitochondrial genetics and the diverse clinical and biochemical symptoms of primary mitochondrial disorders (PMDs) have shown to be a significant obstacle to the development of effective disease-modifying medications. A successful clinical transition of genetic medicines for PMDs is possible, according to encouraging evidence from gene therapy trials in patients with Leber hereditary optic neuropathy and improvements in DNA editing tools.

Cell & Gene Therapy Market Revenue, By Therapeutic Class, 2022-2032 (USD Million)

By Therapeutic Class

2022

2023

2027

2031

2032

Cardiovascular Disease

744.36

882.84

1,780.08

3,697.84

4,460.03

Genetic Disorder

1,643.41

1,922.21

3,665.70

7,202.20

8,566.52

Oncology

1,936.87

2,272.26

4,385.58

8,720.66

10,403.81

Hematology

1,196.56

1,396.75

2,642.34

5,150.06

6,113.36

Ophthalmology

835.60

972.46

1,817.62

3,500.15

4,142.33

Infectious Disease

4,420.18

5,206.30

10,210.05

20,628.98

24,708.86

Neurological Disorders

658.61

777.29

1,536.51

3,129.23

3,755.58

Others

4,028.39

4,693.50

8,802.17

16,973.35

20,087.70

By Delivery Method

The market is split into In Vivo therapy and Ex Vivo therapy according to the type of therapy. In vivo therapy market is anticipated to grow exponentially throughout the projected period. When it comes to gene therapy, there are two different methods: ex vivo and in vivo, setting aside cell therapies. The altered human gene must first enter the diseased person's cells for gene therapy to take effect. There are two methods for doing this; Genetic material is supplied in vivo to afflicted cells (cancer cells or other cells) that are still present within an individual's body. After cells are collected and exposed to the genome in Ex vivo, altered genes are transferred to a person's body.

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Cell and Gene Therapy Market Size to Reach USD 97.33 Bn by 2033 - BioSpace

Recommendation and review posted by Bethany Smith

Advances in the treatment of ophthalmic conditions with gene therapies have led to a growing market with huge potential for the future, according to research from DelveInsight.

The industry analyst has prepared a reportindicating that the market size for gene therapies in ophthalmology reached roughly $132 million across mature markets last year.

Taking into account new therapies expected to come online in future years, this market could grow at

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Research shows stellar growth for gene therapies in ophthalmology - The Pharma Letter

Recommendation and review posted by Bethany Smith

A company started by University of Pennsylvania scientist Jim Wilson has received FDA approval to test a form of gene editing in infants for the first time in the United States, the company said Thursday.

The Plymouth Meeting company, iECURE, is developing a treatment for babies whose livers are unable to make a crucial enzyme.

Infants born with a severe form of the illness can lapse into a coma within a day or two of birth, their brains damaged by a buildup of ammonia. Some die soon thereafter; the rest have little recourse beyond a liver transplant.

This is the same disease that Wilson was studying in a high-profile test that resulted in a patient death in 1999. The patient in that case, Jesse Gelsinger, had a mild form of the disease. The 18-year-old died after his body rejected the virus used to deliver the treatment.

In Wilsons new approach with iECURE, the gene is delivered with a different type of virus that does not trigger the immune system a delivery method that he already has licensed for use in several other drugs.

The treatment had previously been approved for testing in the United Kingdom and Australia, iECURE said. The company is enrolling boys up to 9 months old.

This milestone is the culmination of over 8 years of pre-clinical research in my laboratory addressing gene editing strategies for severe rare liver metabolic diseases, Wilson said in a news release.

Founded in 2022, iECURE raised $65 million from venture capitalists in late 2022. That was during a period of waning investor enthusiasm for cell and gene therapy companies.

Both Penn and Wilson have an unspecified financial interest in iECURE.

See original here:
Penn scientist Jim Wilson's iECURE can start testing gene therapy in infants - The Philadelphia Inquirer

Recommendation and review posted by Bethany Smith

The concept of putting genes into the human body to correct a missing or dysfunctional gene first emerged in the 1960s. Since then, the field of gene therapy has experienced groundbreaking research discoveries, tragic pitfalls, and finally, a resurgence in interest and a rise in breakthroughs.

Download this Science Milestone from Drug Discovery News to learn about the complicated past of early gene therapy discoveries and the technologies that eventually led to gene therapy success.

Original post:
Science Milestone: The evolution of gene therapy - Drug Discovery News

Recommendation and review posted by Bethany Smith