StemCell Therapy

As a new mother, she didnt know to look for blue-tinged lips. She could just tell her babys color was off. On a chest X-ray, the clean, white-against-dark curves of his ribs were obscured, clouded by fluid. Pneumonia. That tipped Ray Ballards physicians off: He had a form of severe combined immunodeficiency SCID, for short a genetic mutation that hampered the growth of crucial immune cells, leaving him utterly vulnerable to infection.

The best fix was a transplant of his mothers bone marrow. The attitude was that in three to six months, you should be able to go back to normal life, recalled his mom, Barb Ballard.

That was true at least sort of. He got two more booster transplants before he hit 10. An antibiotic left him with hearing loss, and a virus with digestive tract damage. His lack of B cells meant he needed regular injections of other peoples antibodies, and his T cell counts were never ideal. But he was healthy enough to go to public school, to move through the hallways high-fiving half the guys, to slowly inhale and take aim during rifle team practice.

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His T cells had to be working well enough that he wasnt coming down with everything that walked into the classroom, Ballard said.

Then, when Ray was around 18, his immunity began to wane. For him, it came in the form of a norovirus he couldnt shake. For others with the same rare disease, it appears as pneumonia or gastrointestinal trouble or an unexpected T cell decline. Over the last 10 years, the trend has become increasingly clear: The bone marrow transplants that kept certain babies with SCID alive sometimes stop working after years or decades of providing fairly reliable immune defenses.

Now, to patient advocates, this has become an urgent lesson in the language people use to talk about treatment and not just for SCID. They see their communitys experience as a cautionary tale for anyone developing or receiving a therapy thats marketed as potentially curative.

Theres an expectation and a hope: When they hear about bone marrow transplants, it sounds like a lifetime deal, a forever fix, said John Boyle, president and CEO of the Immune Deficiency Foundation. Weve discovered, as a result of this issue, that bone marrow transplant ended up not being the forever fix we thought it was.

Experts have known for years that some of these transplants wouldnt provide full immune protection over the course of a SCID patients entire life. They say clinicians should have avoided the word cure. But even scientific papers that hinted at such complications called the treatment curative. Just this year, an Immune Deficiency Foundation employee was given the unenviable task of sifting through the organizations thousands of pages of online material, scrubbing out every cure that popped up. It was only there a handful of times sometimes in quotes from clinicians, Boyle said but it was there and it needed to be removed.

The language patients hear can sometimes even change their outcomes. Weve heard of cases where, years later, they realized their immune system isnt as healthy as they thought, but nobody was tracking that because they hadnt maintained a relationship with the physician, or the physician didnt maintain a relationship with them, explained Ballard. The word cure, it gives them a false sense of security.

At a time when seemingly every biotech is promoting the idea of one-and-done therapies and setting prices accordingly these advocates hope companies, too, will be more wary. One of the things Im trying to make them very aware of is the need for lifelong follow-up, said Heather Smith, who runs the SCID Angels for Life foundation. For her, its personal: This summer, her son took part in a clinical trial for a gene therapy in the hope that it would provide the immune protection that his decades-old bone marrow transplant no longer could. My son will be followed for 15 years, she said. But what about after that?

Part of the issue with bone marrow transplants from one person to another is the natural genetic variation between us, particularly in the proteins that help our bodies distinguish its own cells from foreign ones. Receiving cells from someone whose proteins dont match yours could cause a civil war within you. Thats why bone marrow transplants began back in the 1950s with identical twins: Sharing those genes meant increasing the likelihood of harmony between the body and the graft.

But the vast majority of people dont have a protein-matched sibling, let alone an identical twin. So researchers set about figuring out how to transplant bone marrow from a parent to a child in spite of only sharing half of their genes and from a matched unrelated donor to a stranger. Like cooks intent on refining recipes to their taste, the doctors who adapted the technique for SCID often did so slightly differently from one another. Over the past 35 years, those idiosyncrasies have hardened into habits. Right now, everybody transplants their patients their way, said Dr. Sung-Yun Pai, an immune deficiency researcher and co-director of the gene therapy program at Boston Childrens Hospital.

Perhaps the most vociferous controversy has been about whether to use chemotherapy to wipe out the existing stem cells within a recipients bone marrow to make room for the donors. The doctors who do use chemo before a transplant might prescribe different doses; others forego it entirely.

The arguments were sound on both sides. On the one hand, the toxic drugs could clean out the niches within our bone and increase the chances that the donors cells take root. On the other, these chemicals could hamper growth, brain development, and fertility, could make an infant who was already sick even sicker, and could increase the likelihood of certain cancers later in life. Its like being exposed to a bunch of X-rays and sunlight, or other DNA-damaging agents, Pai explained.

Because SCID is so rare the most common subtype is thought to occur in 1 out of every 50,000 to 100,000 newborns and because every hospital was doing transplants slightly differently, it was hard for physicians to systematically study what was working best. But even early on, they could tell that some of the infants whod gotten no chemo were developing incomplete immune systems. They didnt produce their own B cells, for instance, and so needed regular injections of antibodies collected from other peoples blood.

In healthy infants, stem cells migrate from the crevices of the skeleton to an organ in the chest called the thymus, where theyre trained to become T cells. In these infants, the T cell counts grew after transplant but it wasnt necessarily because the sludge was securely taking hold in the niches of their bones. Rather, immunologists say, the donors progenitor cells were only transient. Some were able to head toward the thymus for schooling. Some graduated and started fighting off infections. But as those populations were depleted with age, there werent robust reserves of stem cells in the bone marrow that could arrive to produce more. To Pai, its like trying to fill a kindergarten class in a neighborhood where no ones having babies.

You and I continue to have a slow trickle of new T cells coming out, said Dr. Harry Malech, a senior investigator at the National Institutes of Health, who sits on the board of a gene therapy company, Orchard Therapeutics (ORTX), but does not receive any financial compensation. Instead of a torrent becoming slower, in these patients it goes from a trickle to practically nothing.

Thats why immunity starts to wane in kids like Ray Ballard. To many immunologists, it isnt a surprise, though they still arent sure why chemo-less transplants last longer for some of these kids than others. They can also understand how some families and clinicians might have viewed this treatment as a lifetime fix.

As Malech put it, If I said to you, Your child, instead of dying in infancy, will likely get to adulthood, go to school, have a normal life, you might think the word cure in your mind.

Even for parents who knew the protection might not last forever, the failure of a long-ago bone marrow transplant puts them in a bind. If they do nothing, their child will once again be vulnerable to any passing infection, which could prove fatal. They can try another round of the same procedure, though booster transplants sometimes come with added complications. Or they can try getting their child into a research trial for gene therapy, which comes with the risks of any experimental treatment.

Some feel an irrational guilt when the bone marrow they donated to their child stops functioning. Its your cells, and if it doesnt work, you failed them, said Ballard, who lives in Clifton, Va., about a 40-minute drive from Washington, D.C. Her son Ray had already had three transplants as a child. When his immune system started to fail again in early adulthood, gene therapy at the NIH seemed like the only reasonable choice.

That would involve researchers removing cells from his bone marrow, using an engineered virus as a kind of molecular syringe to slip in a healthy copy of the gene in which he had a defect, and then threading these corrected cells back into his veins a bone marrow transplant to himself. But preparing a virus can be tricky, and there were delays.

Meanwhile, Rays condition was getting worse. His norovirus was preventing him from absorbing much nutrition, and as Ballard put it, his bone structure was just crumbling at that point. His doctors told her he had the skeleton of an 85-year-old.

He died this past February, at 25 years old. One friend got his birth and death dates tattooed onto her shoulder. Another painted a portrait of him for Ballard, in which his arms are crossed, his lips pressed together in a wry smile.

At Boston Childrens, Pai is now helping to lead a randomized trial to better understand what dose of chemo works best for SCID patients receiving transplants. Over the last decade or so, she, Malech, and many other clinicians have also teamed up to track the long-term results of immune deficient patients whove received someone elses bone marrow.

Pai is hopeful that knowing about the phenomenon of waning immunity will give gene therapies a better shot at becoming a durable fix. They probably have a better chance of achieving a one-time, lifelong cure, but its never wrong to be humble, she said. Only after decades more and hundreds or thousands of patients will we know for sure.

Patient advocates point out that even then, these patients will still have the capacity of passing on their SCID-causing gene to future generations, and so the word cure is overly optimistic. Thats why I like the word remission, said Smith. That still gives you the hope. If you were given a cancer diagnosis, you wouldnt go through treatment and then just forget about it for the rest of your life.

As Boyle put it, Weve seen the promise and then weve seen the reality. Everyone who is looking at a transformational therapy should be optimistic, but also realistic, and not assume that this is truly one and done. (Boyles foundation has received financial support from Orchard Therapeutics, which is developing a gene therapy for a form of SCID.)

To Amy Saada, of South Windsor, Conn., that isnt theoretical. Her son Adam is now 12, and the immunity from the bone marrow transplant he got as a baby is wearing off. He isnt yet sick, but his parents know they need to decide between gene therapy or another transplant soon. She has a very clear memory of how long and uncertain the recovery from treatment felt. In some ways, she wishes she didnt know quite as much as she does; that way, she would feel less trepidation about what lies ahead.

Your heart kind of sinks, she said. Youve already been through it once, and it was hell. Its harder the second time.

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Waning treatment is a warning for all 'one-and-done' therapies - STAT - STAT

Neveah Taouk, 4

At last, when Mary was seven and Neveah three, new developments in whole-genome sequencing enabled specialists to identify the disorder. The diagnosis gave the Taouks information but not hope. They knew what the problem was, but there was no treatment and no cure.

Desperate, Charlie contacted specialists around the world. I must have spoken to at least fifty people scientists, doctors, professors, he says. Most of them had never heard of the condition.

His search eventually led to Dr Wendy Gold, a specialist in rare genetic disorders in children, based at the University of Sydney and the Childrens Hospital at Westmead. We arranged to talk, says Charlie. To be honest, I wasnt expecting much. But then she said, Have you heard of gene therapy?

Gene therapy is a new and rapidly evolving field of research. One of the therapys forms involves adding new genes to a patients cells to replace missing or malfunctioning genes. The new genes are typically delivered to the appropriate cells in the body using a benign virus as a carrier. Gene therapy is already being used to treat diseases including spinal muscular atrophy. It could also be a promising treatment for Parkinsons disease. Dr Gold believed there was a chance it could help the Taouk girls.

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The gene therapy research that could save a family of four - News - The University of Sydney

CAMBRIDGE, Mass.--(BUSINESS WIRE)--bluebird bio, Inc. (NASDAQ: BLUE) today announced that members of the management team will present at the following upcoming investor conferences in January:

To access the live webcasts of bluebird bios presentations, please visit the Events & Presentations page within the Investors & Media section of the bluebird bio website at http://investor.bluebirdbio.com. Replays of the webcasts will be available on the bluebird bio website for 90 days following the events.

About bluebird bio, Inc.bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

bluebird bio is a trademark of bluebird bio, Inc.

Forward-Looking StatementsThis release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the advancement of, and anticipated development and commercialization plans for, the Companys product candidates. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risks that the preliminary positive efficacy and safety results from our prior and ongoing clinical trials of our product candidates will not continue or be repeated in our ongoing or planned clinical trials; risks that the current or planned clinical trials of our product candidates will be insufficient to support future regulatory submissions or to support marketing approval in the U.S. and EU; and the risk that our product candidates will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled Risk Factors in our most recent Form 10-Q as well as discussions of potential risks, uncertainties and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

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bluebird bio Announces Investor Events in January - Business Wire

Indian Council of Medical Research (ICMR) is setting up a task force on gene therapy research to encourage research in the emerging field.

The research body among other things has proposed forming the task force to explore gene editing based therapeutic approaches to treat illnesses.

In a call for research proposals, ICMR has stressed that many inherited disorders are not treated by current available drugs or traditional therapies.

Gene Therapy refers to the process of introduction, removal or change in content of an individuals genetic material with the goal of treating the disease and a possibility of achieving long term cure.

While the western world has made considerable strides with regards to gene therapy over the past 30 years, ICMR stated that drugs like Luxuturna for Retinitis Pigmentosa, a condition which leads to breakdown of retinal cells in the eye, and leads to low vision, or Yescarta which is a cell therapy for cancer, are currently in clinical trial phase.

However for the vast majority of inherited diseases, appropriate targeted therapies are yet unavailable despite the large load of genetic disease in our population. To address this particular gap, ICMR is inviting proposals to fund gene therapy research projects, the research body has said in its circular.

ICMR has narrowed down on genetic diseases affecting the brain and muscles, eye disorders affecting the retina and cornea, heart diseases and blood disorders like Thalassemia, Sickle Cell Disease and Haemophilia. It has also stressed on diseases like Cancer, Diabetes and Lung diseases. The strategies proposed shuold have a possibility of translation into future human trials, the circular states.

In recently released guidelines on gene therapy ICMR stated, India has large burden of genetic disorders and unmet medical needs and gene therapy can prove to be a turning point in treatment of such disorders. However, it also brings along with it unique technical risks and ethical challenges. Creation of babies using germline gene editing by a Chinese scientist recently, attracted global criticism and fuelled a debate on ethical concerns regarding applications of gene therapy technologies. This also brought to forefront the requirement of stringent guidelines and regulations to prevent misuse and premature commercialization.

It further said, Many countries around the world have developed rules and guidelines to regulate gene therapy trials. Taking cognizance of situation, it was felt necessary to frame national guidelines and regulations to direct scientists and clinicians including industry regarding the procedures and requirements to be followed for performing gene therapy in India.

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ICMR sets up a task force on gene therapy research - BusinessLine

Earlier this year, the US Food and Drug Administration approved the most expensive drug ever to hit the market, a gene therapy for spinal muscular atrophy. SMA is a neuromuscular disorder that, in severe cases, can lead to infant death. The genetic correction is currently used to treat affected newborns, but as symptoms for some types of SMA may appear before birth, an earlier treatment would be potentially more effective.

In a study published December 4 in Molecular Therapy, researchers were able to fix a mutation in the survival motor neuron 1 (SMN1) genewhich causes SMA in humansin mice modelling the disease, while they were still inside their mothers uterus. The treated mice lived longer and had fewer symptoms than untreated animals.

Tippi MacKenzie, a fetal and pediatric surgeon at the University of California, San Francisco, who did not participate in this study, says it is an important paper because it is the first time fetal gene therapy has succeeded in SMA mice. Before you even think about doing something in patients, you have to first do it in the disease model of the mouse . . . so this group has supplied a very important piece to the literature, she adds.

SMN1encodes an essential protein for the maintenance of motor neurons, which are nerve cells in the brain and spinal cord responsible for controlling muscle movement. The result in children with mutations in the gene is the loss of motor neurons, leading to muscle weakness and associated complications. SMA affects one out of every 6,000 to 10,000 babies.

Correcting the SMN1 sequence is a potentially efficient treatment for those born with SMA. Zolgensma, the recently approved medication for this disorder, consists of an intravenous administration of an adeno-associated virus that ferries a functional copy of the SMN1 gene to the brain.

To see if the same fix could be accomplished before birth, the research team tested two different injection methods: one into the placenta (intraplacental or IP) and the other into one of the brain lateral ventricles (intracerebroventricular or ICV). The latter proved to be more effective. By injecting the viral vector into the fetuss brain, the virus will go directly into the cerebrospinal fluid, and it will transduce motor neurons in the spinal cord with a very high efficiency, compared to the IP [injection], says Afrooz Rashnonejad. who participated in this study while working at Ege University in Izmir, Turkey, but has recently moved to Nationwide Childrens Hospital in Columbus, Ohio.

Rashnonejad and her colleagues then monitored the injected mice that were carried to term. Those treated with the vector carrying a functional copy of SMN1 lived a median lifespan of 63 or 105 days (depending on the type of cassette carrying the gene), much longer than untreated SMA mice, which did not survive more than 14 days, but still less than wildtype pups, which had a median lifespan of 405 days. The treated mice were also heavier than untreated mice, but smaller than healthy mice.

The investigators also observed differences at the cellular and molecular levels. SMN protein levels were completely recovered in the brain and spinal cord, and the number of motor neurons was higher in treated animals.

I was just very impressed by what theyve done, says Simon Waddington, a gene therapy researcher at University College London who did not participate in this work, but was one of the reviewers of the paper. He adds that he and other colleagues had previously tried fetal gene therapy on SMA mice, but had failed as it is a technically difficult experiment. So it was really nice to see this group actually did a really good job.

This is the first time viral vectors have been used to successfully boost gene expression in SMA mice before birth. Interventions to edit the genome in utero have been previously used in mice that model other severe genetic diseases. Last year, for instance, Waddington and colleagues used fetal gene therapy to treat mice affected by Gaucher disease, a neurodegenerative disorder that can be fatal for newborns. Other successful attempts include intrauterine gene editing for mice affected by -thalassemia, an inherited blood disorder, and mice suffering a monogenic lung disease that normally results in newborn death.

MacKenzie says that, in a recent national meeting on in utero gene therapy, it was discussed how to move forward with a clinical application to the FDA. We are definitively moving towards that direction, but we dont have a particular application yet, because its still not clear which disease should be the first.

SMA makes a lot of sense because its so severe, MacKenzie adds. But at the same time, the results that are coming out at conferences, she observes, suggest that newborn babies receiving Zolgensma are doing pretty well, better than anybody could have imagined. So its not clear that you have to go before birth. A good candidate, she explains, would be a very rare type of SMA, where the baby dies before birth.

Waddington says that researchers might have to wait for neonatal gene therapy to become standard for certain diseases before using fetal gene therapy in humans. Once we actually understand how efficient this is, and if we come to the point where we discover that the earlier that you go the more effective it is . . . in a human setting, then we may be able to do fetal gene therapy. I think that we are looking at more than five years away before thats even likely to happen, he hypothesizes.

A. Rashnonejad et al., Fetal gene therapy using a single injection of recombinant AAV9 rescued SMA phenotype in mice,Molecular Therapy, 27:212333, 2019.

Alejandra Manjarrez is a freelance science journalist. Email her atalejandra.manjarrezc@gmail.com.

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Fetal Gene Therapy Helps Mice with Spinal Muscular Atrophy - The Scientist

Gene therapy, once dismissed as too dangerous, has made a comeback, with two products approved in the U.S. since December 2017 and hundreds more in the pipeline. STATs latest report takes a deep dive into a crucial component of these new treatments: the viral vectors used to deliver gene therapies to cells and organs.

As dozens of new gene therapies near the market, we spoke with academic experts, pioneers in the field, and executives with 18 companies, large and small, to identify the most important challenges surrounding the engineering of better vectors, their safety, effectiveness, efficiency, production, and cost and how key players are thinking about overcoming those hurdles.

These engineered viruses are difficult to manufacture, particularly at the massive scale needed for some indications. Scientists are working hard to bring down the cost and speed up the process of making viral vectors, so that all the patients that could benefit from gene therapy will have access to it.

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Beyond the introduction, this report has four major components:

The basics of viral vectors and the history of their development;

Major challenges in the development, manufacturing, and testing of viral vectors, and possible solutions;

A close look at the status of gene therapies in 10 disease categories that are advancing through preclinical studies or are being tested in early-stage clinical trials;

And perspective on the U.S. Food and Drug Administrations approach to regulating viral vectors.

The report The STAT guide to viral vectors, the linchpin of gene therapy is intended for anyone with a strong interest in gene therapy, including biotech executives, investors, scientists, lawyers, policymakers, and patients and families interested in learning more. Our aim is to make the problems, stakes, and possibilities clear to everyone.

To buy the full report, please click here.

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New STAT report explores viral vectors, the linchpin of gene therapy - STAT - STAT

Law360 (December 11, 2019, 1:28 PM EST) -- The gene therapy industry is in an exciting phase of growth, undergoing significant mergers and acquisitions activity, product sales and new marketing authorizations that are being issued with increasing regularity globally.

Recent reports have estimated that the market is likely to be almost four times its current value by 2025[1], with up to 20 new product approvals expected every year[2].

This rapid growth brings inevitable challenges. Significant issues relating to regulatory standards in manufacturing plants, establishing acceptable reimbursement policies and antitrust investigations are among a few.

The intellectual property landscape has been lower profile, with the exception of the ongoing CRISPR...

In the legal profession, information is the key to success. You have to know whats happening with clients, competitors, practice areas, and industries. Law360 provides the intelligence you need to remain an expert and beat the competition.

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The Rise Of Patent Wars In Europe's Gene Therapy Space - Law360

Fox News senior judicial analyst Judge Andrew Napolitano on the potential fallout from reports DNA-testing company Family TreeDNA will share data with the FBI in an effort to solve crimes.

Libella Gene Therapeutics is charging volunteers $1 million to undergo clinical trials of a treatment it is working on that is designed to prevent, delay or even reverse aging.

However, participants will be required to go to a small clinic in Cartagena, Colombia, to participate, which the Kansas-based company said was the easiest site among eight different countries it looked into, calling it the path of least resistance.

In a press release, a company executive said traditional clinical trials in the U.S. take years and millions or even billions of dollars.

The treatment would be delivered intravascularly and participants will be monitored over the course of a year, according to the company's website. Gene therapy treatments are intended to be one-off treatments, attacking the problem at its source.

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The technology focuses on lengthening telomeres, which are structures found at the end of chromosomes. Their main function is to protect DNA during cell division.

Every time a cell divides, a part of the telomere is lost until it becomes too short and the cell dies. Some believe that as cells age, so does the body.

Telomerase is an enzyme that lengthens telomeres and thus prevents the cell from dying.

Libellas technology rebuilds the ends of telomeres, andthereby affects the aging process.

I know what were trying to do sounds like science fiction, but I believe its a science reality, Jeff Mathis, CEO of Libella Gene Therapeutics, said in an interview with OneZero.

The treatment may potentially treat other diseases, like cancer and Alzheimers.

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Not everyone, however, agrees that lengthening telomeres will have any effect on the aging process. For example, researchers at the University of Utah were unable to conclude whether shorter telomeres were simply a sign of aging or actually a contributor to the process.

Dr. Andrew Stern, who is one of the founders of Libella Gene Therapeutics, was also one of the principal discoverers of portions of human telomerase.

In order to be eligible for the trial, individuals must be 45 years or older. So far the company has recruited two people, according to the OneZero interview published on Medium.

The study will look into the change in the length of telomeres, and into the incidence of serious adverse events.

The FDA declined to comment specifically on Libella Gene Therapeutics and its decision to hold its trial outside of the U.S. It does, however, accept foreign clinical data and results so long as certain conditions are met.

A spokesperson for Libella Gene Therapeutics did not return FOX Business request for comment.

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Would you pay $1M to partake in an anti-aging gene therapy trial? - Fox Business

An effective andinnovative way to treat people with sickle cell anemia using gene therapy may soon be available thanks to efforts by several pharmaceutical companies, a Bloomberg report says.

Sickle cell anemia, a genetic defect that causes red blood cells to form in theshape ofa sickle, hinders the bodys ability to adequately distribute oxygen. This is due to atypical hemoglobin molecules, which is the protein in blood that transports oxygen. Sickle cell disease can be extremely painful, causing blood cells to get trapped in blood vessels and lead to heart failure, debilitating fatigue, strokes and blood clots.About 100,000 people suffer from sickle cell anemia in the U.S,with African Americansbeing disproportionately affected by this condition.

New developments with gene therapy, however, could work to have a positive impact on these symptoms. One of the innovative manufacturers, Bluebird Bio, stole the show at the annual conference of the American Society of Hematology in Florida. Its product, LentiGlobin, debuted positive results; in 17 patients treated with LentiGlobin,more than 40 percent of the hemoglobin in patients' red blood cells appearedin a healthier form thanks to gene therapy, per the article.

Bluebird isnt the only biotechnology making strides in gene therapies. Another potential treatment being researched is based on the technology called CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), a gene-editing tool that is being used for a wide range of biomedical applications.

Documented in an NPR report, sickle cell patient Victoria Gray recently became the first person in the U.S. to have billions of her own cells genetically edited with CRISPR and reintroduced into her body. These cells will hopefully produce fetal hemoglobin to compensate for the faulty hemoglobin in Grays red blood cells. The trial is being expanded to include more patients and is being conducted by Vertex Pharmaceuticals and CRISPR Therapeutics of the Boston area.

Current treatments for sickle cell include blood and bone marrow transfusions and medication. Studies on gene therapy treatments have been encouraging so far, but there is more testing to be done before either CRISPR or LentiGlobin hits the market.

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Gene therapy could be a revolutionary new treatment for sickle cell disease - The Hill

One of the most popular methods for inserting therapeutic genes into cells to treat disease is to transport them using a virus that has been stripped of its infectious properties. But those noninfectious viruses can still sometimes touch off dangerous immune responses.

A team from Johns Hopkins Medicine is proposing an alternative method for transporting large therapies into cellsincluding genes and even the gene-editing system CRISPR. Its a nano-container made of a polymer that biodegrades once its inside the cell, unleashing the therapy. The researchers described the invention in the journal Science Advances.

The team, led by biomedical engineer Jordan Green, Ph.D., was inspired by viruses, which have many properties that make them ideal transport vehicles. They have both negative and positive charges, for example, which allows them to get close to cells. So Green and his colleagues developed a polymer containing four molecules with both positive and negative charges. They used it to make a container that interacts with the cell membrane and is eventually engulfed by it.

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The Hopkins researchers performed four experiments to prove the nanocontainers would travel into cells and deliver complex therapies once inside. First, they packaged a small protein into the polymer material and mixed it with mouse kidney cells in a lab dish. Using fluorescent tags, they confirmed that the protein made it into the cells. Then they repeated the experiment with a much larger medicinehuman immunoglobulinand observed that 90% of the kidney cells received the treatment.

From there, they made the payload even bulkier, packaging the nanocontainers with the gene-editing system CRISPR. With the help of fluorescent signals, they were able to confirm that CRISPR went to work once inside the cells, disabling a gene 77% of the time.

"That's pretty effective considering, with other gene-editing systems, you might get the correct gene-cutting result less than 10 percent of the time," said graduate student Yuan Rui in a statement.

Finally, the Hopkins researchers injected CRISPR components into mouse models of brain cancer using the polymer nanocontainers. Again they saw evidence that successful gene editing had occurred.

Developing improved methods for gene therapy is a priority in the field. In October, for example, scientists at Scripps Research described a way to use a small molecule called caraphenol A to lower levels of interferon-induced transmembrane (IFITM) proteins, which could, in turn, allow viral vectors to pass more easily into cells. And earlier this year, an Italian team described a method for including the protein CD47 in lentiviral vectors to improve the transferring of therapeutic genes into liver cells.

The next step for Hopkins researchers Rui and Green is to improve the stability of the nanocontainers so they can be injected into the bloodstream. They hope to be able to target them to cells that have certain genetic markers, they reported.

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Hopkins team invents non-viral system for getting gene therapy into cells - FierceBiotech

Pfizer moved into gene therapies earlier than some of its peers, partnering with Spark Therapeutics in 2014 and paying close to $200m (180m) upfront to acquire Bamboo Therapeutics two years later. The Bamboo takeover gave Pfizer ownership of a manufacturing facility in North Carolina, US.

Earlier this year, Pfizer doubled down on in-house production of gene therapies, committing $500m to expand its footprint in North Carolina.

Talking at a recent investor conference, Mikael Dolsten, chief scientific officer at Pfizer, said the spending commitment is, in part, a reflection of a belief that keeping production in-house will deliver better results than relying on third parties.

Dolsten said, When we compare that with what we get from other companies, we think we can really improve the yield, the purity and the characterization of the product.

Across the industry, poor yields have exacerbated capacity constraints created by the rapid expansion of the gene therapy pipeline, turning quality manufacturing capacity into a sought after resource.

A desire to possess in-house manufacturing capacity was a factor in many of the recent acquisitions of gene therapy companies, such as Astellas $3bn takeover of Audentes Therapeutics.

Gene therapy startups, such as Audentes and Bamboo, bypassed the limitations of contract capacity by establishing internal capabilities. Those capabilities enabled the companies to advance their gene therapies and, ultimately, to attract takeover offers, but their creation required the sort of upfront investments in infrastructure that many venture-backed startups typically try to avoid.

Through its $500m gene therapy investment, Pfizer thinks it can provide an alternative for startups that are struggling to access high-quality contract capacity but are unable or unwilling to build their own facilities.

Dolsten said, We think it's a competitive advantage, not just for our product, but for companies that want to partner with Pfizer that may allow them to have an easier and more high-end dialogue with regulators across the globe about this new field and a new type of product.

If Dolsten is right, the North Carolina manufacturing capacity could give Pfizer an edge when it tries to partner with gene therapy startups that have other options open to them, such as alliances with rival drugmakers and contract manufacturing organizations.

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Pfizer to bring gene therapy production in-house - BioPharma-Reporter.com

Abstract / Synopsis:

Two anti-VEGF gene therapies are being investigated in clinical trials of patients with exudative age-related macular degeneration. Initial efficacy and safety results are encouraging.

Anti-VEGF gene therapy for exudative age-related macular degeneration (AMD) has transformative potential for reducing treatment burden and improving patient outcomes, according to Szilrd Kiss, MD.

Two investigational anti-VEGF gene therapies are currently being investigated in clinical trialsRGX-314 (Regenxbio) and ADVM-022 (Adverum). Dr. Kiss described the two technologies and reviewed some preliminary clinical trial results that support their promise for providing sustained benefit with a single injection.

Considering the treatment burden of anti-VEGF therapy for other ocular diseases, we can imagine that exudative AMD is just the first indication that will be targeted for anti-VEGF gene therapy, said Dr. Kiss, chief, Retina Service, associate professor of ophthalmology, and associate dean at Weill Cornell Medical College, New York, NY.

RGX-314 delivers a gene for an anti-VEGF fab protein that is similar to ranibizumab. It uses adeno-associated virus-8 (AAV8) as a vector and is administered in the operating room as a subretinal injection.

AAV is the most common viral vector carrier used for gene therapy. Different AAV serotypes have different tissue selectivity, Dr. Kiss explained. AAV8 is a wild type AAV that has the propensity for greater transfection of retinal cells compared with AAV2 following subretinal gene therapy delivery.

RELATED:AAO 2019: Encouraging results revealed from early trial of subretinal gene therapy for wet AMD

Disclosures:

Szilrd Kiss, MDe: [emailprotected]This article was adapted from Dr. Kiss presentation at the 2019 meeting of the American Academy of Ophthalmology. Dr. Kiss is a consultant to RegenxBio and Spark Therapeutics and is a consultant and equity owner in Adverum.

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Research targets gene therapy for exudative AMD patients - Modern Retina

Dr. James Wilson is a pioneer in gene therapy. That does not mean he is necessarily impressed with the current state of affairs.

In five years, when we look back on the way were executing on gene therapy now, were going to realize that things are going to be very different, Wilson said at the STAT Summit in Cambridge, Mass., recently. The way in which were going to treat Duchenne muscular dystrophy, potentially cure it, is not the way in which its being evaluated in the clinic now.

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Dr. James Wilson, a scientific pioneer, on the future of gene therapy - STAT - STAT

Its said that nothing is certain except death and taxes. But doubt has been cast over the former since the 1970s, when scientists picked at the seams of one of the fundamental mysteries of biology: the molecular reasons we get old and die.

The loose thread they pulled had to do with telomeresmolecular timepieces on the ends of chromosomes that shorten each time a cell divides, in effect giving it a fixed life span. Some tissues (such as the gut lining) renew almost constantly, and it was found that these have high levels of an enzyme called telomerase, which works to rebuild and extend the telomeres so cells can keep dividing.

That was enough to win Elizabeth Blackburn, Carol Greider, and Jack Szostak a Nobel Prize in 2009. The obvious question, then, was whether telomerase could protect any cell from agingand maybe extend the life of entire organisms, too.

While telomere-extending treatments in mice have yielded intriguing results, nobody has demonstrated that tweaking the molecular clocks has benefits for humans. That isnt stopping one US startup from advertising a telomere-boosting genetic therapyat a price.

Libella Gene Therapeutics, based in Manhattan, Kansas, claims it is now offering a gene therapy to repair telomeres at a clinic in Colombia for $1 million a dose. The company announced on November 21 that it was recruiting patients into what it termed a pay-to-play clinical trial.

Buyer beware, though: this trial is for an unproven, untested treatment that might even be harmful to your health.

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The company proposes to inject patients with viruses carrying the genetic instructions cells need to manufacture telomerase reverse transcriptase, a molecule involved in extending the length of telomeres.

The dangers are enormous, says Jerry Shay, a world expert on aging and cancer at the University of Texas Southwestern Medical Center. Theres a risk of activating a pre-cancerous cell thats got all the alterations except telomerase, especially in people 65 and over.

For years now, people involved in the company have made shifting claims about the study, raising uncertainty about who is involved, when it might start, and even where it would occur. Trial listings posted in October to clinicaltrials.gov currently show plans for three linked experiments, each with five patients, targeting critical limb ischemia, Alzheimers, and aging, respectively.

Jeff Mathis, president of Libella, told MIT Technology Review that two patients have already paid the enormous fee to take part in the study: a 90-year-old-woman and a 79-year-old man, both US citizens. He said they could receive the gene therapy by the second week of January 2020.

The decision to charge patients a fortune to participate in the study of an experimental treatment is a red flag, say ethics experts. Whats the moral justification for charging individuals with Alzheimers? asks Leigh Turner, at the University of Minnesotas Center for Bioethics. Why charge those bearing all the risk?

The telomere study is occurring outside the US because it has not been approved by the Food and Drug Administration. Details posted to clincaltrials.gov indicate that the injections would be carried out at the IPS Arcasalud SAS medical clinic in Zipaquir, Colombia, 40 kilometers (25 miles) north of Bogot.

It takes a lot longer, is a lot more expensive, to get anything done in the US in a timely fashion, Mathis says of Libellas choice to go offshore.

To some promoters of telomerase gene therapy, urgency is justified. Heres the ethical dilemma: Do you run fast and run the risk of low credibility, or move slowly and have more credibility and global acceptancebut meanwhile people have died? says Mike Fossel, the president of Telocyte, a company planning to run a study of telomerase gene therapy for Alzhheimer's in the US if it can win FDA signoff.

Our reporting revealed a number of unanswered questions about the trial. According to the listings, the principal investigatorwhich is to say the doctor in charge--is Jorge Ulloa, a vascular surgeon rather than an expert in gene transfer. I dont see someone with relevant scientific expertise, says Turner.

Furthermore, Bill Andrews, who is listed as Libellas chief scientific officer, says he does not know who Ulloa is, even though on Libellas website, the mens photos appear together on the list of team members. He said he believed that different doctors were leading the trial.

Turner also expressed concerns about the proposed 10-day observation period described in the posting for the overseas study: If someone pays, shows up, has treatment, and doesnt stick around very long, how are follow-up questions taking place? Where are they taking place?

Companies seeking to try the telomere approach often point to the work of Maria Blasco, a Spanish scientist who reported that telomere-lengthening gene therapy benefited mice and did not cause cancer. Blasco, director of the Spanish National Centre for Cancer Research, says she believes many more studies should be done before trying such a gene experiment on a person.

This isnt the first time Libella has announced that its trial would begin imminently. It claimed in late 2017 that human trials of the telomerase therapy would begin in the next few weeks. In 2016, Andrews (then partnered with biotech startup BioViva) claimed that construction of an age reversal clinic on the island nation of Fiji would be complete before the end of the year. Neither came to pass.

Similar questions surround Libellas most recent claims that it has two paying clients. Pedro Fabian Davalos Berdugo, manager of Arcasalud, said three patients were awaiting treatment in December. But Bioaccess, a Colombian contract research organization facilitating the Libella trial, said that no patients had yet been enrolled.

Also unclear is where Libella is obtaining the viruses needed for the treatment. Virovek, a California biotech company identified by several sources as Libellas manufacturer, did not answer questions about whether any treatment had been produced.

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Buyer beware of this $1 million gene therapy for aging - MIT Technology Review

An American biotech company has launched clinical trials in Colombia to test a new therapy designed to reverse the aging process, and in turn, treat age-related diseases, according to news reports.

But to steal a sip from this purported fountain of youth, participants in the trial must first fork over $1 million a fee that seems even more astronomical when you consider that most clinical trials are either free or provide participants with financial compensation, according to a report by OneZero, a Medium publication about tech and science.

The pricey trial is being run by Libella Gene Therapeutics, a Kansas-based company whose website proclaims that "the future is here." The company announced its intention to test its anti-aging remedies in Cartagena, Colombia, in 2018, and began recruiting for the trials in October of this year. Using a single-gene therapy, Libella aims to "prevent, delay, or even reverse" the general effects of aging, as well as treat diseases that emerge in old age, such as Alzheimer's, according to ClinicalTrials.gov.

In fact, in its own press release, the company boasted, without evidence, that its gene therapy "may be the world's first cure for Alzheimer's disease." The bold claim raises an obvious question: Will the treatment actually work?

Short answer: No one really knows, but the fact that Libella shipped its operation beyond the reach of the U.S. Food and Drug Administration (FDA) doesn't inspire confidence, experts told OneZero.

Related: 5 Reasons Not to Fear Getting Older

Unlike anti-aging face creams that soften the superficial signs of aging, the Libella therapy aims to reverse aging from the ground up, so to speak, starting at the level of our genes. Specifically, the gene therapy is intended to lengthen patients' telomeres structures that cap the tips of chromosomes and prevent the genetic material inside from fraying. Telomeres grow shorter each time a cell divides, and when the structures reach a critical length, cells either stop dividing or perish, according to Stanford Medicine.

The theory goes, if you rebuild the body's shortened telomeres, the process of aging might be thrown in reverse. This is not a new idea. Several studies in mice suggest that using gene therapy to lengthen telomeres can reverse certain signs of aging in the animals. A 2015 study from Stanford prompted similar effects in isolated human cells; the treatment lengthened cells' telomeres by fiddling with a close cousin of DNA, called RNA, which helps cells build proteins.

The Libella therapy aims to help cells rebuild telomeres by activating a gene in their DNA that would normally be switched "off." The gene, called TERT, contains instructions to build a protein called "telomerase," an enzyme that adds molecules to the end of telomeres and prevents the structures from shortening during cell replication, according to a 2010 report in the journal Biochemistry.

Libella's lead scientific officer, molecular biologist William Andrews, originally helped identify the human telomerase enzyme at the biotech firm Geron. Later, he licensed a gene therapy based on the finding to Libella, according to OneZero. "I can't say [telomere shortening is] the only cause of aging, but it plays a role in humans," Andrews told the publication.

Related: 8 Tips for Healthy Aging

Andrews' therapies will soon be put to the test in Colombia, where one 79-year-old will receive the anti-aging treatment in next month, according to OneZero. The anti-aging trial will include four more participants over age 45 and focus on verifying that the treatment is "safe and tolerable," meaning it does not harm patients or cause unacceptable side effects.

Two more trials will use the same therapy but aim to "prevent, delay, or even reverse the development" of Alzheimer's disease and critical limb ischemia, an age-related condition in which a person's arteries become severely obstructed. Participants in these trials must already be diagnosed with the disorders.

After treatment, participants in all three trials will remain in the clinic for 10 days for further monitoring, and then return at regular intervals for checkups over the following year.

Libella's gene therapy involves a one-time injection delivered through an IV; the Alzheimer's therapy uses the same formula but doctors inject the product into the patient's spinal fluid. Within the product, a modified virus carries the TERT gene into cells and injects the genetic material into their DNA. The modified viruses cannot transmit diseases to people, but in high enough doses, the germs could provoke a harmful immune response in the patient, according to a 2018 animal study. Libella representatives declined to say how high a dose their clinical trial participants will receive.

"All I can say is, it's a lot," Andrews told OneZero.

Potential side effects aside, the fact that the Libella treatment will be administered beyond the purview of the FDA is telling, according to one expert. Leigh Turner, a bioethicist at the University of Minnesota, told OneZero that "even though the company is based in the United States, they've managed to find a way to evade U.S. federal law by going to a jurisdiction where it's easier to engage in this activity."

The $1 million entry fee is also alarming, Turner said, given that most clinical trials don't charge patients anything to enter. Andrews told OneZero that the fee is justified because it costs the company hundreds of thousands of dollars to make enough product to treat just one person.

The appearance of the trials on ClinicalTrials.gov, an official registry maintained by the National Institutes of Health, does not boost their credibility, she added. The automated database can be easily manipulated and "can basically be used as a marketing platform," she said.

Other stakeholders in the telomere-lengthening business are concerned, too. Michael Fossel, founder and president of the biotech startup Telocyte, told OneZero that his company's own therapy is similar to the Libella treatment the difference is that Telocyte is seeking approval through the FDA. "We're afraid that something will go wrong [with the Libella trials], whether it's from a safety or efficacy standpoint," he said.

Related: Extending Life: 7 Ways to Live Past 100

But even in a best case scenario, wherein no patients come to harm, the Libella therapy still might not deliver any notable health benefits. Some research suggests that no link exists between telomere length and aging.

For instance, a study published this year examined more than 261,000 people between age 60 and 70, and found no correlation between participants' telomere lengths and their age-related health outcomes, including their overall cognitive function, muscular integrity and the age of their parents. Long telomeres were associated with a lowered risk of coronary heart disease as compared with short telomeres, but longer telomere length was also linked to a heightened risk of cancer.

"Telomere lengthening may offer little gain in laterlife health status" and lead to an increased risk of cancer, the authors noted.

It remains to be seen whether Libella has truly tapped the fountain of youth, but given the dubious nature of their clinical trials, potential participants may want to exercise caution before relocating to Colombia and shelling out $1 million for a chance to live longer.

Originally published on Live Science.

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New Anti-Aging Clinical Trial Begins. For $1 Million, You Can Be a Participant. - Livescience.com

Dec. 11, 2019 14:00 UTC

BERKELEY, Calif.--(BUSINESS WIRE)-- GenEdit Inc., a developer of a novel polymer nanoparticle technology platform for non-viral- and non-lipid-based delivery of gene therapies, today announced that it has entered into a worldwide, exclusive license and collaboration agreement with Editas Medicine, Inc., a leading genome editing company. GenEdit has developed a comprehensive delivery system for CRISPR-based therapeutics, including gene knockout and gene repair therapies, to enable safer delivery options with improved efficiency.

"This license and collaboration agreement further validates the strength of our intellectual property portfolio and the potential of GenEdits technology," said Kunwoo Lee, Ph.D., co-founder and chief executive officer of GenEdit. "We are pleased to establish our relationship with Editas Medicine as they leverage our technology to develop potential genomic medicines."

Under the terms of the agreement, GenEdit has granted Editas Medicine an exclusive worldwide license, with rights to sublicense, to GenEdits Cpf1-based technologies. In return for these rights, GenEdit will receive undisclosed upfront and development milestone payments, including royalties on net sales of products incorporating the licensed intellectual property. In addition, GenEdit and Editas Medicine will collaborate on evaluating delivery of Cpf1-based technologies with GenEdits nanoparticle platform. Editas Medicine will provide research funding and have an option to continue development after the initial collaboration period.

GenEdits nanoparticle platform consists of a proprietary non-viral, non-lipid library of polymers that efficiently encapsulate and deliver cargo [RNA, DNA, protein and/or ribonucleic acid-protein complexes (RNP)] to specific tissues. The company screens the library to identify initial hits and then uses computational analysis and medicinal chemistry for iterative lead optimization. The company has used this platform to identify multiple candidate polymers for efficient and specific delivery of gene editing to a range of tissues.

"Compared to viral vectors and lipid-based nanoparticles, our approach has the potential for better targeting, more cargo, and lower manufacturing cost," said Timothy Fong, Ph.D., chief scientific officer of GenEdit. "In particular, our approach has the potential to enable in vivo gene editing of multiple tissues with CRISPR and expand the potential of gene therapies to treat more diverse sets of diseases."

About GenEdit

GenEdit was founded to transform the delivery of gene and gene editing therapies. We have synthesized the NanoGalaxy library of polymers that can encapsulate RNA, DNA, protein and/or RNP. Through advanced screening methods, computational analysis and iterative medicinal chemistry, we have demonstrated efficient delivery of gene editing cargo to specific tissues. We seek development partnerships for specific tissues and/or gene targets while advancing our internal pipeline of gene editing therapies.

For more information, please visit http://www.genedit.com.

View source version on businesswire.com: https://www.businesswire.com/news/home/20191211005025/en/

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GenEdit and Editas Medicine Enter into Exclusive License and Collaboration Agreement for Nanoparticle Gene Therapy Delivery - BioSpace

A gene therapy for bladder cancer that recently received $400 million in support from the private equity company Blackstone Group helped more than half of treated patients with resistant disease achieve remission.

The therapy, called nadofaragene firadenovec, was discovered by a Finnish-based research institute and first entered clinical study in 2012. The data revealed today at the Society of Urologic Oncology meeting came from a Phase 3 trial that is part of the agent's Biologics License Application now before the FDA.

Licensed by its original owner, FKD Therapies Oy, to Switzerland-based Ferring Pharmaceuticals, nadofaragene firadenovec is now in the hands of the U.S. subsidiary FerGene. That company was created with the Blackstone investment and an additonal $170 million from Ferring. FerGene will commercialize the gene therapy in the U.S., with Ferring holding rights elsewhere.

Nadofaragene firadenovec is an an adenovirus-based gene therapy encoding production of the immunity-stimulating protein interferon alfa-2b. Viral vectors containing the gene are administered by catheter once every three months into the bladder, where they are absorbed into cells in the organ's walls and begin stimulating interferon.

Delivery through a catheter, called intravesical administration, limits systemic exposure to both the viral vectors and to inteferon, said Neal Shore, medical director for the Carolina Urologic Research Center and an investigator in the trial.The side-effects of interferon include flu-like symptoms in patients who inject it for other conditions like multiple sclerosis.

The clinical trial enrolled 157 patients with bladder cancer that has not spread to muscle walls and has stopped responding to treatment with Bacillus Calmette-Gurin vaccine.

Alternative treatments for these patients include chemotherapy or a procedure called "complete cystectomy." This surgery entails complete removal of the bladder, which in men means removal of the prostate and seminal vesicles and in women the uterus, ovaries, fallopian tube and part of the vagina.

"Radical cystectomy is one of the most invasive surgeries we do not just in urology but in all of surgery," Shore said, requiring a lengthy hospital stay and having a high rate of post-procedural complications.

Out of a group of 103 patients with superficial tumors in the bladder wall, just over half were in complete remission at three months, 41% at six months, and 24% at one year. In a group of 48 patients whose cancer had spread to the connective tissue outside the bladder, 73% had no recurrence of serious disease at three months, which fell to 44% at 12 months.

In this type of bladder cancer, the FDA has said a single-arm trial, without a placebo control, using complete remission is sufficient to be considered for approval, and the study does not need to pre-specify a rate that would define success. "The natural history of [disease]is well understood, and the complete response rate is negligible in the absence of therapy," the agency said in guidelines published in February 2018.

One chemotherapy agent, called Valstar (valrubicin), is approved for this patient group. It won FDA approval on a complete response rate of 18%.

In seeking FDA approval, nadofaragene firadenovec is in a race with Merck & Co.'s Keytruda (pembrolizumab) to achieve approval first. That immuno-oncology agent tested Keytruda in a similar population in the Keynote-057 trial, in which it achieved a 39% complete response rate.

Keytruda will be the subject of a meeting of the FDA's Oncologic Drugs Advisory Committee on Dec. 17.

Aside from the remission rates,Shore said nadofaragene firadenovec would differentiate itself from Keytruda in practice because its intravesical delivery means it could be administered by community-based urologists at outpatient clinics.

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Cancer gene therapy backed by Blackstone gets trial win - BioPharma Dive

In the summer, a mother in Nashville with a seemingly incurable genetic disorder finally found an end to her suffering -- by editing her genome.

Victoria Gray's recovery from sickle cell disease, which had caused her painful seizures, came in a year of breakthroughs in one of the hottest areas of medical research -- gene therapy.

"I have hoped for a cure since I was about 11," the 34-year-old told AFP in an email.

"Since I received the new cells, I have been able to enjoy more time with my family without worrying about pain or an out-of-the-blue emergency."

Over several weeks, Gray's blood was drawn so doctors could get to the cause of her illness -- stem cells from her bone marrow that were making deformed red blood cells.

The stem cells were sent to a Scottish laboratory, where their DNA was modified using Crispr/Cas9 -- pronounced "Crisper" -- a new tool informally known as molecular "scissors."

The genetically edited cells were transfused back into Gray's veins and bone marrow. A month later, she was producing normal blood cells.

Medics warn that caution is necessary but, theoretically, she has been cured.

"This is one patient. This is early results. We need to see how it works out in other patients," said her doctor, Haydar Frangoul, at the Sarah Cannon Research Institute in Nashville.

"But these results are really exciting."

In Germany, a 19-year-old woman was treated with a similar method for a different blood disease, beta thalassemia. She had previously needed 16 blood transfusions per year.

Nine months later, she is completely free of that burden.

For decades, the DNA of living organisms such as corn and salmon has been modified.

But Crispr, invented in 2012, made gene editing more widely accessible. It is much simpler than preceding technology, cheaper and easy to use in small labs.

The technique has given new impetus to the perennial debate over the wisdom of humanity manipulating life itself.

"It's all developing very quickly," said French geneticist Emmanuelle Charpentier, one of Crispr's inventors and the cofounder of Crispr Therapeutics, the biotech company conducting the clinical trials involving Gray and the German patient.

Crispr is the latest breakthrough in a year of great strides in gene therapy, a medical adventure started three decades ago, when the first TV telethons were raising money for children with muscular dystrophy.

Scientists practising the technique insert a normal gene into cells containing a defective gene.

It does the work the original could not -- such as making normal red blood cells, in Victoria's case, or making tumor-killing super white blood cells for a cancer patient.

Crispr goes even further: instead of adding a gene, the tool edits the genome itself.

After decades of research and clinical trials on a genetic fix to genetic disorders, 2019 saw a historic milestone: approval to bring to market the first gene therapies for a neuromuscular disease in the US and a blood disease in the European Union.

They join several other gene therapies -- bringing the total to eight -- approved in recent years to treat certain cancers and an inherited blindness.

Serge Braun, the scientific director of the French Muscular Dystrophy Association, sees 2019 as a turning point that will lead to a medical revolution.

"Twenty-five, 30 years, that's the time it had to take," he told AFP from Paris.

"It took a generation for gene therapy to become a reality. Now, it's only going to go faster."

Just outside Washington, at the National Institutes of Health (NIH), researchers are also celebrating a "breakthrough period."

"We have hit an inflection point," said Carrie Wolinetz, NIH's associate director for science policy.

These therapies are exorbitantly expensive, however, costing up to $2 million -- meaning patients face grueling negotiations with their insurance companies.

They also involve a complex regimen of procedures that are only available in wealthy countries.

Gray spent months in hospital getting blood drawn, undergoing chemotherapy, having edited stem cells reintroduced via transfusion -- and fighting a general infection.

"You cannot do this in a community hospital close to home," said her doctor.

However, the number of approved gene therapies will increase to about 40 by 2022, according to MIT researchers.

They will mostly target cancers and diseases that affect muscles, the eyes and the nervous system.

Another problem with Crispr is that its relative simplicity has triggered the imaginations of rogue practitioners who don't necessarily share the medical ethics of Western medicine.

Last year in China, scientist He Jiankui triggered an international scandal -- and his excommunication from the scientific community -- when he used Crispr to create what he called the first gene-edited humans.

The biophysicist said he had altered the DNA of human embryos that became twin girls Lulu and Nana.

His goal was to create a mutation that would prevent the girls from contracting HIV, even though there was no specific reason to put them through the process.

"That technology is not safe," said Kiran Musunuru, a genetics professor at the University of Pennsylvania, explaining that the Crispr "scissors" often cut next to the targeted gene, causing unexpected mutations.

"It's very easy to do if you don't care about the consequences," Musunuru added.

Despite the ethical pitfalls, restraint seems mainly to have prevailed so far.

The community is keeping a close eye on Russia, where biologist Denis Rebrikov has said he wants to use Crispr to help deaf parents have children without the disability.

There is also the temptation to genetically edit entire animal species -- malaria-causing mosquitoes in Burkina Faso or mice hosting ticks that carry Lyme disease in the US.

The researchers in charge of those projects are advancing carefully, however, fully aware of the unpredictability of chain reactions on the ecosystem.

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Charpentier doesn't believe in the more dystopian scenarios predicted for gene therapy, including American "biohackers" injecting themselves with Crispr technology bought online.

"Not everyone is a biologist or scientist," she said.

And the possibility of military hijacking to create soldier-killing viruses or bacteria that would ravage enemies' crops?

Charpentier thinks that technology generally tends to be used for the better.

"I'm a bacteriologist -- we've been talking about bioterrorism for years," she said. "Nothing has ever happened."

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A #ReUp of 2019: The year when gene therapy, DNA modifications came of age & saved lives - Economic Times

On the heels of an FDA speedy review for Keytrudas potential use in non-muscle invasive bladder cancer (NMIBC), its close rival, a gene therapy by Ferring Pharmaceuticals spinout FerGene, has posted late-stage data. By the looks of it, the two drugs are up for a fight.

Among patients with high-risk NMIBC superficial disease thats unresponsive to standard-of-care Bacillus Calmette-Gurin (BCG), nadofaragene firadenovec eliminated tumors in 53%, or 55 of 103 patients,at month three in a phase 3 study, FerGene unveiled Thursday at the Society of Urologic Oncology meeting.

By comparison, in Keytrudas own registrational trial on the same target patient population, the Merck & Co. PD-1 completely cleared tumors in 41.2%, or 42 of 102 patients, after three months, according to an update at the European Society for Medical Oncology annual meeting in September.

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The length of time responses lasted appeared similar between the two drugs in their separate studies. For Keytruda, 24 patients (23.5%) continued to show no signs of disease after a year. As for nadofaragene firadenovec, 24.3%, or 25 patients, were still tumor-free at month 12.

In terms of safety, Keytruda recorded Grade 3/4 side effects in12.7% of patients, while FerGene said there were no Grade 4/5 events in its study.

We are pleased with these Phase 3 data results, including the complete response rates and favorable safety profile seen with nadofaragene firadenovec, Nigel Parker, scientific founder of FKD Therapies, said in a statement. The data have also helped FKD'snew drug application earn an FDA priority review.

RELATED:Merck's Keytruda is bound for new bladder cancer territory. But can it hold up against gene therapy?

Ferring recently gained commercial rights to the gene therapy from FKD, and, with $400 million in help from Blackstone Life Sciences, spun it into FerGene. Interestingly, it was Merck that licensed the drugout to FKD in the first place in 2011 in return for an equity stake in the then-newly formed Finnish company.

Priority reviews in hand, the two companies could be looking at FDA approvals soon. The burning question is, how does FerGene plan to price a gene therapy, which belongs to a class of drug thats notoriously costly? In a statement sentto FiercePharma, Ferring said it's too early to discuss pricing, that its top priority is still to get nadofaragene firadenovec approved andinvest into R&Dto study the product in more indications.

Keytruda is meant to be given ata fixed dose every three weeks. Nadofaragene firadenovec, which uses an adenovirus vector to deliver the gene interferon alfa-2b to stimulate an innate immune response to fight cancer, is administered into the bladder every three months.

Merck does have an upper hand against FerGene. The Big Pharma has been the sole supplier of BCG in the U.S. and several other key markets globally for several years now. So, it could offer BCG and Keytruda as a one-two punch for NMIBC, similar to the wayBayer is billing Nexavar and Stivarga as a part of the same continuumin first- and second-line liver cancer.

RELATED:Merck limits orders for bladder cancer drug as demand outstrips supply

There are other players eyeing the same patient population. Sesen Bio has Vicinium, an antibody-drug conjugate that targets epithelial cell adhesion molecule antigens on the surface of tumor cells to deliver a toxin payload. In its own phase 3 trial dubbed Vista also in high-risk, BCG-unresponsive NMIBC, Vicinium eradicated tumors in 40% of 89 patients at month three, according to an update the company provided in August. However, its response seems to wane over time more quickly than its rivals', as only 17% of patients showed no signs of tumor activity after 12 months.

The Cambridge, Massachusetts-based biotech recently held two meetings with the FDA and confirmed a submission process, including the design for a post-marketing confirmatory trial. It would enroll BCG-refractory patients who, because of supply constraints, haven't received an optimal BCG dose, which the company said represents a broader patientpopulation in light of anongoing shortage.

Sesen now expects to submit a biologics license application under rolling review by year-end with potential approval in 2020.

As for its pricing, during a presentation at the H.C. Wainwright investor conference in September, Sesens president and CEO Thomas Cannell pointed out that PD-1/L1s would cost about $150,000 to $200,000 per patient per year in NMIBC.

Weve done two rounds of market research with payers, and they think thats reasonable, he said. They think at those levels, there will probably be minimal prior authorization or step edits in terms of restricting a treatments use.

Assuming an official launch in 2021, Jefferies analysts, in a Nov. 12 note to clients, pegged $167.5 million for Viciniums U.S. sales in 2024. Before the priority designation, SVB Leerinks Daina Graybosch predicted a Keytruda launch in NMIBC in 2022 and forecastU.S. sales of $250 million in the indication for the Merck PD-1 inhibitor in 2025.

Editor's Note: The story has been updated with a statement from Ferring Pharma.

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Bayersinvestigationalgene therapy BAY 2599023 safely and effectively increased the levels ofclotting factor VIII (FVIII) and prevented or lessened bleeding in the first two people with severe hemophilia A treated ina Phase 1/2 clinical trial, preliminary data show.

The ongoing trial (NCT03588299; 2017-000806-39) is enrolling up to 30 eligible adult patients. More information, including recruiting sites in the U.S. and Europe, is availablehere.

These early results will be presented in the poster, First-in-human Gene Therapy Study of AAVhu37 Capsid Vector Technology in Severe Hemophilia A, at the 61st American Society of Hematology (ASH) Annual Meeting & ExpositionrunningDec. 710 in Orlando, Florida.

BAY 2599023 initially by Dimension Therapeutics as DTX201 is being developed by Bayer in collaboration with Ultragenyx Pharmaceuticals. The potential gene therapy aims to promote a sustained production of FVIII and overcome its deficit in hemophilia A patients, reducing or eliminating the need for prophylatic, or preventive, FVIII replacement therapy and the occurrence of bleeding events.

Administered as a single infusion, the therapy uses a modified and harmless version of the adeno-associated virus (AAV), called AAVhu37, to deliver a shorter but functionalcopy of the FVIII gene to liver cells, where clotting factors are produced. This version of the FVIII gene is known as B-domain deleted FVIII gene.

Preclinical studies showed that AAVhu37 effectively delivered the FVIII gene to liver cells, had a favorable distribution, and induced a durable FVIII production.

In addition, preclinical data showed that BAY 2599023 had a good safety profile, and the potential to promote FVIII production to levels considered to be therapeutic over a long period of time.

The ongoing, dose-establishingPhase 1/2 trial (NCT03588299; 2017-000806-39) is evaluating the safety, tolerability and early effectiveness of three ascending doses of BAY 2599023 in adult men with severe hemophilia A who have been previously treated with FVIII products.

It is the first clinical trial to evaluate a gene therapy based on the AAVhu37.

Up to 30 enrolled patients will be given a single intravenous infusion of one of three doses of BAY 2599023. The studys primary goal is to measure safety through reports of adverse events. Secondary goals include measuring FVIII activity and assessing the number of patients who reach more than 5% of FVIII production at six and 12 months after treatment at the different doses.

Data on the first two men treated at BAY 2599023s starting dose (0.5 x 1013 gene copies/kg) will be presented at the meeting. These men had more than 150 days of treatment with FVIII products, no history of FVIII inhibitors, and no detectable immune response against AAVhu37.

No adverse events were reported after more than 15 weeks of safety evaluations (about four months). Blood levels of liver enzymes also remained within a normal range, and either of these patients needed to be treated with corticosteroids.

The first man reached a stable FVIII production of around 5%, and was free of bleeding events or a need for prophylactic treatment for six weeks. The second patient, who had 99 bleeds in the year before receiving the gene therapy, reached a stable FVIII production of around 17%, and has been bleed-free for more than 5.5 months (at the time of data collection).

These preliminary data suggest that BAY 2599023 is safe and effective in promoting the production of FVIII and in reducing or preventing the occurrence of bleeding events and the need for prophylactic treatment, the researchers wrote.

Overall, data generated from this first dose cohort demonstrate that successful translation from pre-clinical to clinical development and proof-of-mechanism for BAY 2599023 was achieved, they concluded.

Marta Figueiredo holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from the University of Lisbon, Portugal. She is currently finishing her PhD in Biomedical Sciences at the University of Lisbon, where she focused her research on the role of several signalling pathways in thymus and parathyroid glands embryonic development.

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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Tcnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.

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First 2 Adults with Severe Hemophilia A Respond Well to Gene Therapy BAY 2599023 in Clinical Trial - Hemophilia News Today