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Category Archives: Gene Medicine

Novel Switch Promises Safer Gene Therapy On-Demand – Mirage News

Just like a doctor adjusts the dose of a medication to the patient's needs, the expression of therapeutic genes, those modified in a person to treat or cure a disease via gene therapy, also needs to be maintained within a therapeutic window. Staying within the therapeutic window is important as too much of the protein could be toxic, and too little could result in a small or no therapeutic effect.

Although the principle of therapeutic window has been known for a long time, there has been no strategy to implement it safely, limiting the potential applications of gene therapy in the clinic. In their current study published in the journal Nature Biotechnology, researchers at Baylor College of Medicine report on a technology to effectively regulate gene expression, a promising solution to fill this gap in gene therapy clinical applications.

"Although there are several gene regulation systems used in mammalian cells, none has been approved by the U.S. Food and Drug Administration for clinical applications, mainly because those systems use a regulatory protein that is foreign to the human body, which triggers an immune response against it," said corresponding author Dr. Laising Yen, associate professor of pathology and immunology and of molecular and cellular biology at Baylor. "This means that the cells that are expressing the therapeutic protein would be attacked, eliminated or neutralized by the patient's immune system, making the therapy ineffective."

For more than a decade, Yen and his colleagues have been working on this technology and now they have found a solution to overcome the main obstacles in its clinical use. "The solution we found does not involve a foreign regulatory protein that will evoke an immune response in patients. Instead, we use small molecules to interact with RNA, which typically do not trigger an immune response," Yen said. "Other groups also have made attempts to resolve this critical issue, but the drug concentrations they used are beyond what the FDA has approved for patients. We were able to engineer our system in such a way that it works at the FDA-approved dosage."

A switch to turn genes on/off on cue

Yen and his colleagues developed a system that turns genes on to different levels on cue using small molecules at FDA-approved doses. The switch is placed in the RNA, the copy of genetic material that is translated into a protein. This approach allows the researchers to control the protein's production a step back by controlling its RNA.

The RNA of interest is first engineered to contain an extra polyA signal, akin to a "stop sign" that genes naturally use to mark the end of a gene. When the machinery of the cell detects a polyA signal in the RNA, it automatically makes a cut and defines the cut point as the end of the RNA. "In our system, we use the added polyA signal, not at the end, but at the beginning of the RNA, so the cut destroys the RNA and therefore the default is no protein production. It is turned off until we turn it on with the small molecule," Yen said.

To turn on the gene at the desired level, the team engineered a switch on the RNA. They modified a section of the RNA near the polyA signal such that it can now bind to a small molecule, FDA-approved tetracycline in this case. "When tetracycline binds to that section that functions as a sensor on the RNA, it masks off the polyA signal, and the RNA will now be translated into protein," Yen said.

Imagine the now possible future situation. A patient has received gene therapy that provides a gene to compensate for a malfunctioning gene that causes a medical condition. The gene the patient received has the switch, which allows the physician to control the production of the therapeutic protein. If the patient only requires a small amount of the therapeutic protein, then he/she will only take a small dose of tetracycline, which will turn on the therapeutic gene only a little. If the patient needs more therapeutic protein, then he/she would take more tetracycline to boost production. To stop production of the therapeutic protein, the patient stops taking tetracycline. In the absence of tetracycline, the switch will be back to its default off position. Some diseases may benefit from the presence of constant low levels of therapeutic protein. In that case, the technology has the flexibility to pre-adjust the default level to specified levels of protein expression while retaining the option of dialing up the expression with tetracycline.

"This strategy allows us to be more precise in the control of gene expression of a therapeutic protein. It enables us to adjust its production according to disease's stages or tune to the patients' specific needs, all using the FDA-approved tetracycline dose," Yen said. "Our approach is not disease-specific, it can theoretically be used for regulating the expression of any protein, and potentially has many therapeutic applications. In addition, this system is more compact and easier to implement than the existing technologies. Therefore, it also can be very useful in the lab to turn a gene of interest on or off to study its function."

Liming Luo, Jocelyn Duen-Ya Jea, Yan Wang and Pei-Wen Chao, all at Baylor College of Medicine, also contributed to this work.

This work was supported by an E&M Foundation Pre-Doctoral Fellowship for Biomedical Research, NIH grants (R01EB013584, UM1HG006348, R01DK114356, R01HL130249, P30 CA125123 and S10 RR024574), Biogen SRA, seed fund from Department of Pathology and Immunology at Baylor College of Medicine and CPRIT Core Facility Support Award CPRIT-RP180672.

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Can Europe afford the next generation of medicines? – POLITICO Europe

On the face of it, medical science has delivered at just the right time.

Europes population is growing older: by 2100 nearly a third of people will be aged 65 or over. A major challenge for this century is how to keep people healthy.

At the same time, the last decade has seen personalized medicines come within reach. Cell and gene therapies tailored to individual patients can cure diseases, from fixing misfiring biology to training the immune system to kill cancer cells.

But with price tags of up to 3 million per treatment,healthsystems simply arent designed to absorb these kinds of hits.

The question now is whether Europe will be able to square the circle and take full advantage of the new therapies. Or will budget constraints keep these medical advances out of reach?

To date, the European Commission has authorized 25 cell and gene therapies for use in Europe.

These therapies involve careful manipulation and growth of human cells to be given often as one-off treatments and in some cases cures for debilitating and often deadly rare diseases and certain types of cancer. Novartis Kymriah, a CAR-T therapy that delivers genes into the body to tell the immune system to attack and kill blood cancer cells, is one such example.

These medicines are often tailor-made for a single patient, making them extremely expensive.

Novartis Zolgensma, a gene therapy for children with spinal muscular atrophy, had a U.S. list price of $2.1 million for a one-off dose when it was approved in May 2019 (it was approved in the EU in May 2020). Since then, it has lost the title of the worlds most expensive therapy to CSL Behrings hemophilia B gene therapy Hemgenix, a one-off infusion that costs $3.5 million a dose.

Big upfront costs in building the first manufacturing facilities for these types of therapies play a role in high prices, said Matthew Durdy, chief executive of the Cell and Gene Therapy Catapult, an independent nonprofit that brings together academia, industry, health services and government to deliver these products in the U.K.

But these costs will come down, he said, just as they do with every new technology, from mobile phones to laptops. For that to happen, health systems must start using the therapies. Without a market, competitors will not follow, and without competition, prices wont drop.

But thats easier said than done.

Finding a price that is both affordable to health care payers and profitable for companies is a major and significant challenge, said Tim Hunt, chief executive of the Alliance for Regenerative Medicine (ARM), which represents developers of these therapies.

And its one which has pushed companies to shutter some EU operations and investors to hold back, he said. Seven of the 25 cell and gene therapies approved in Europe have already been withdrawn by drugmakers from EU markets.

Since 2018, the EU cell and gene therapy market has grown just 11 percent, compared with 43 percent in the U.S. and 531 percent in China.

Consequently, EU patients are losing out on the next generation of treatments, Hunt said.

One way to bring things back on track is delivering data that shows a particular therapy works and justifies those initial high costs. But this data can be hard to come by.

Thats because it takes years to prove that a drug prevents a progressive disease, for example. And in rare conditions, there are only a handful of patients to test out new therapies, limiting the evidence.

Therefore, to approve these therapies, Europe has been steadily lowering the bar for clinical evidence, said Lydie Meheus, managing director at the not-for-profit research organization the Anticancer Fund.

While this authorizes more therapies, lack of data creates significant problems for payers asking health systems to take big financial risks when resources are especially stretched, staff are on strike and services are still grappling with pandemic backlogs.

We really need to rebalance the scale when it comes to the evidence generation of these types of products, said Yannis Natsis, chief executive of the European Social Insurance Platform (ESIP). Limited data and high prices are a huge challenge for payers, he said.

One hope lies in Europes 2021 Health Technology Assessment (HTA) regulation.

From 2025, all cell and gene therapies will undergo a single EU assessment of the value they add to patients and health systems, hopefully ending the need for 27 duplicate reviews. This recommendation will be used by payers in each country in their pricing talks with developers.

Companies will also meet jointly with the European Medicines Agency and Europes HTA coordinating group to thrash out the best clinical trial designs that deliver data, not only on safety and efficacy but also on added value.

And the technology is rapidly progressing. While the majority of cell and gene therapies involve taking a patient sample and tailor-making a treatment, in time the aim is to deliver more products that are developed without the need of a patient sample.

A lot of companies are trying to focus more on in vivo gene therapies [where the genetic changes happen inside the body as opposed to in a lab] and off-the-shelf cell therapies that use donor materials, said Stephen Majors, head of communications at ARM.

This will lessen the production costs, curtailing the need for the intensive process of removing a patients cells, sending them elsewhere to be modified, and using cold chain storage infrastructure, he said.

And if the longer-term data bears fruit on curative benefits, payers may be more willing to pay. Some are already adapting payment models to spread the costs over several years.

To Durdy, at the U.K. catapult, these types of therapies will save money in the long run. Spending for example $2 million to $3 million on curing a hemophilia patient will prevent up to $12 million in lifetime care costs for that patient, he said.

He imagined that, in the future, payers would think along the following lines: Its going to blow my budget this year. But if all of these therapeutics come through, Im going to transform the way I do health care.

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Can Europe afford the next generation of medicines? - POLITICO Europe

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Researchers solve mystery of how statins improve blood vessel health – Stanford Medical Center Report

ATAC-seq revealed that simvastatin-treated cells had closed chromatin structures that reduced the expression of genes that cause the endothelial-to-mesenchymal transition. Working backward, the researchers found that simvastatin prevents a protein known as YAP from entering the nucleus and opening chromatin.

The YAP protein is known to play important roles in development, such as regulating the size of our organs, but also has been implicated in the abnormal cell growth seen in cancer.

To see the drug in context, the researchers tested simvastatin on diabetic mice. Diabetes causes subtle changes to blood vessels that mimic the damage commonly seen in people who are prescribed statins older patients who do not have a cardiovascular condition, Liu said.

They found that after eight weeks on simvastatin, the diabetic mice had significantly improved vascular function, with arteries that more easily relaxed and contracted.

If we can understand the mechanism, we can fine-tune this drug to be more specific to rescuing vascular function, Liu said.

The findings also provide a more detailed picture of the vascular disease process, which could help doctors identify and treat early signs of vascular damage.

Ive been taking statins for the past 10 years to keep my cholesterol down. I also knew it has good vascular effects. I just didnt know how it does it, said Wu, the Simon H. Stertzer, MD, Professor who is also the director of the Stanford Cardiovascular Institute. This study explains how.

Researchers from the University of North Texas and the Ohio State University College of Medicine contributed to this study.

The study was supported by funding from the National Institutes of Health (grants R01 HL130020, R01 HL150693, R01 HL163680, R01 HL145676, P01 HL141084, R01 HL141371, R01 HL126527, R01 HL15864, R01 HL161002, R01 HL155282 and 18CDA34110293), an American Heart Association SFRN grant, an AHA Career Development Award and the Tobacco-Related Disease Research Program.

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Researchers solve mystery of how statins improve blood vessel health - Stanford Medical Center Report

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Autism-related genes converge on microglia and dopamine in … – Spectrum – Autism Research News

Mutations in any of 10 genes strongly linked to autism have several converging effects on brain size, activity and behavior in zebrafish via pathways that involve the proliferation of dopamine neurons and microglia, according to a new study.

None of the mutations cause identical changes. But their varied effects on brain size occur largely in the forebrain and cerebellum, and their influence on activity comes mainly from the thalamus and dopamine neurons, the study shows. And all 10 genes cluster into three groups based on how they affect the sleep and sensory-processing behaviors of zebrafish.

We were able to identify subgroups of autism genes that share related behavioral features, says lead investigator Ellen Hoffman, associate professor in the Child Study Center at Yale University. Were hoping in future studies to leverage these subgroups to identify potential pharmacological targets using a precision medicine approach.

Hoffman and her colleagues used gene-editing tools to introduce damaging mutations into autism-linked genes that are known to have diverse functions: CHD8, CUL3, KDM5B, POGZ and TBR1 regulate gene expression; CNTNAP2, SCN1LAB (the zebrafish version of SCN1A and SCN2A) and GRIN2B facilitate communication among neurons; and DYRK1A and KATNAL2 are involved with cell-structure components, including microtubules and cytoskeletons.

The team uncovered the points of convergence by analyzing more than 7,500 larval zebrafish in a battery of tests: They imaged each animals brain structure and volume, stained a protein called phosphorylated ERK as a proxy of brain activity, and used automated motion-tracking cameras to monitor the larvas sleep-wake cycles and observe its responses to sudden light or dark exposures. The findings were published in Cell Reports in March.

The approach of this work is exactly where we need to be these days, says Helen Willsey, assistant professor of psychiatry and behavioral sciences at the University of California, San Francisco, who was not involved in the new study. Were starting to understand how these seemingly disparate genes actually do similar things during brain development, and then being able to leverage that to figure out how to reverse it.

Hoffmans team studied the DYRK1A and SCN1LAB models in further depth, because those two showed the greatest changes across all the assays.

Both models significantly downregulated genes associated with neurogenesis and dopamine signaling, RNA sequencing showed. They also have a decrease in the number of dopamine neurons in the forebrain.

High throughput: Hoffman and her team examined thousands of zebrafish larvae in 96-well plates, including this one.

The fish also showed upregulation of microglia-associated genes and greater numbers of microglia throughout the entire brain. Increased microglia expression can boost synaptic pruning and may explain the reduced brain volume seen in the two models.

This convergence suggests that there could be common druggable targets for autism subtypes that were not previously known to be related, says Holly Stessman, assistant professor of pharmacology and neuroscience at Creighton University in Omaha, Nebraska, who was not involved in the study. Taking individual genes and going down the rabbit hole is going to be the way that we are now going to move the field a big pace forward, Stessman says.

The study is thorough and high quality, but it also reflects some limitations of the methods used in the autism genetics field, says Hazel Sive, dean of the College of Science at Northeastern University in Boston, Massachusetts, who was not involved in the work. For instance, all the animals in this study had two nonfunctional copies of the gene in question, but people with the same variant tend to only have one, with the other remaining intact.

Hoffman and her colleagues are now screening drugs on the subgroups with similar behavioral profiles to see if any molecules can address multiple genetic models. They are also imaging the brains of live fish to observe dopamine circuit development and investigating the mechanisms that contribute to the global increases in microglia.

Cite this article: https://doi.org/10.53053/THAB6590

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Autism-related genes converge on microglia and dopamine in ... - Spectrum - Autism Research News

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‘The luckiest of the unlucky’: A Duchenne gene therapy brings hope … – BioPharma Dive

The diagnosis was news no parent ever wants to receive. Susan and Chris Finazzo heard it twice in two months.

Both of their children, Chase and Dylan, have a genetic disease called Duchenne muscular dystrophy. The progressive condition slowly and unstoppably lays waste to muscles, first stealing away the ability to walk, then weakening the lungs and heart.

The hopes they held for their childrens future were darkened by fears of a shortened life, and dread of when Chase and Dylan would no longer be able to climb a playground slide, dress independently or swallow food.

Youre just sitting there like, this is not what was supposed to happen, Susan said. Youre mourning the death of the life that you thought your child was going to have.

The Finazzos didnt accept the outlook doctors gave their sons, though. They trawled through the internet looking for answers to their many questions. They met with patient advocates to learn about experimental medicines being developed, and enrolled Chase and Dylan in a clinical trial of a cutting-edge gene therapy.

We always say were the luckiest of the unlucky, she said. This gives us hope.

The Finazzos are part of a large network of parents and patient advocates who believe the gene therapy, developed by biotechnology company Sarepta Therapeutics, represents a medical breakthrough for Duchenne. The treatment is an infusion meant to change the course of the disease for years, if not permanently. Available medicines, by comparison, are thought to only slow Duchennes relentless advance, not halt it, as a gene therapy might.

There isnt a parent, family or person with this diagnosis that doesn't go to bed every night and say, Stop the disease right here. Let it be stopped, said Pat Furlong, president and CEO of Parent Project Muscular Dystrophy, a prominent patient advocacy group. The community believes this is a very important step forward.

Sarepta has asked the Food and Drug Administration for an accelerated approval, a type of clearance thats used to speed treatments for serious diseases like Duchenne to market. The companys case is supported by data showing its drug produces large amounts of a potentially helpful protein, as well as signs some study participants are doing better than medical history suggests they should.

I am not, as I sit here today, aware of an approved therapy under the accelerated approval pathway with more compelling evidence than we have, said Sarepta CEO Doug Ingram.

Yet the treatment failed an important part of its only placebo-controlled test to date. The effects of the protein it helps produce, a diminutive molecule called microdystrophin, arent fully understood. Nor is how long any benefit might last. An approval, if granted, would set a precedent for other gene therapy developers to follow, raising the stakes of the agencys decision.

The FDA is expected to issue its verdict by the end of May, about six months before a Phase 3 study will deliver results that either confirm or refute the benefit of a treatment likely to cost more than $1 million. The regulator is convening a group of outside experts on Friday to discuss it a meeting reportedly scheduled because of intra-agency disagreement about the strength of Sareptas application.

This is a very, between a rock and a hard place situation for the FDA, said Dae Gon Ha, an analyst at the investment bank Stifel, who covers gene therapy companies.

Tim Revell embraces his then 8-year-old son Timothy after running the Austin Marathon.

Permission granted by Tim Revell

Seventeen years ago, Tim Revells son Timothy was having trouble walking.

A whirlwind of brain and blood tests followed, confirming that Duchenne was why Timothy, then 2, had fallen behind his peers. The Revells doctor told Tim that all he could do was go home and love his son.

Timothy is one of an estimated 300,000 people worldwide, almost exclusively boys, who have the condition, which is caused by a genetic mutation that stops the body from making a muscle-protecting protein called dystrophin. A few years later, the Revells learned Timothys younger brother had it too.

Parents of children with Duchenne have long received the same advice as Revell heard in 2006. Theres zero hope, he recalls being told.

Revell became an advocate for drug research and got his sons into earlier clinical trials of Duchenne medicines that ultimately proved unhelpful. In the meantime, he's watched the disease slowly take hold. Timothy lost the ability to walk three years ago.

Duchenne is like death by 1,000 cuts, he said. After years of decline, death often occurs in young adulthood, when the muscles of the heart or lungs fail.

There are a few treatments available. Some patients with particular mutations can get drugs known as exon-skippers, which help the body produce a shortened form of dystrophin thats thought but not proven to modestly slow progression. Others, like Revells sons, arent eligible.

However, most rely on steroids, which can slow muscle damage but cause other problems like weight gain, weak bones and behavioral changes.

It's not a great choice, and it's not an easy one for parents to make, said Jennifer Handt, whose 5-year-old son Charlie has Duchenne. The expectation is to hopefully buy a little bit of time until science can give us something more tangible.

For decades, patient advocates have put their hopes in gene therapy, a way of shuttling replacements for missing or damaged genes into the body to restore needed proteins like dystrophin. Until recently, it had always seemed just out of reach.

I remember in my first meeting 30 years ago, it was raised, At some point we'll have gene therapy, said PPMDs Furlong, and it sounded way back then like, Oh my gosh, what will it take to get there?

Necrotic muscle fiber is associated with Duchenne.

Jose Luis Calvo Martin, Jose Enrique Garcia-Maurino Muzquiz via Getty Images

Jerry Mendell saw his first Duchenne patient in 1969, during a postdoctoral fellowship at the National Institutes of Health.

We didn't know anything about the disease then, he said. Just what it looked like under a microscope.

What started as a fellowship became a lifelong mission for Mendell, who in the following decades emerged as a top researcher in the field of neuromuscular disease.

In 1989, he and his team at Ohio State University published research that established the steroid prednisone as the standard of care for Duchenne. In the late 1990s, he was the first to test a gene therapy for another neuromuscular condition in humans and later conducted an early gene therapy experiment in Duchenne. More than a decade later, after Mendell became director of gene therapy research at Nationwide Childrens Hospital, the team he assembled invented Zolgensma, a dramatically beneficial medicine for infants born with the rare condition spinal muscular atrophy.

I understood the potential for gene therapy if we could make it work for Duchenne, he said. There were many scientists and clinicians who doubted it, but to me it was the best approach we had.

Duchenne presents several vexing scientific problems, however.

Jerry Mendell

Permission granted by Nationwide Children's Hospital

The disease has been seen as a target for gene therapy since the 1980s, when its genetic roots were first identified. But the gene that encodes for dystrophin is too large to be packaged into the microscopic viruses researchers use to deliver corrective gene therapy. And because Duchenne affects muscle, researchers need to use very high doses to shuttle in enough genetic material to hope for a benefit.

This disease is a significant adversary, said John Brandsema, a pediatric neurologist at the Childrens Hospital of Philadelphia. We have been hammering away at it for decades.

Scientists have spent years searching for workarounds, dissecting the gene and trying to figure out how to make it small enough to fit into the virus, Mendell said.

The solution was found in people with a milder form of the condition known as Becker muscular dystrophy. Patients with Becker have a large deletion in the middle of their dystrophin gene, but are still able to make a shorter version of the protein, explained Timothy Lotze, a pediatric neurology professor and director of a muscular dystrophy care center at Texas Children's Hospital. Published research has described a Becker patient who, while missing nearly half of that gene, was still walking at 61 years old.

Those insights sparked a rush among rival research groups to develop gene therapies built around micro or mini forms of the dystrophin gene, many of which were later licensed to or acquired by biopharmaceutical companies.

One program from the laboratory of Jude Samulski at the University of North Carolina was picked up by Pfizer. Another, from Jeff Chamberlain at the University of Washington and Dongsheng Duan at the University of Missouri, ended up in the hands of a biotech called Solid Biosciences.

Nationwides work, co-invented by Mendell and one of his recruits, Louise Rodino-Klapac, was acquired by Sarepta. It was a decision made by former CEO Ed Kaye, who had unsuccessfully tried to license Zolgensma years earlier.

I knew Jerry would be first in the clinic and get it done quickly, he said in a 2019 interview with Xconomy. In this business, its who gets there first thats important.

Charlie Handt, now 5, smiles at his home in Darien, Connecticut.

Permission granted by Jennifer Handt

Jennifer Handt wrestled with whether to enroll her son Charlie in one of Sareptas trials.

She met with other parents, visited different trial sites and did her homework, including vetting the doctor who would treat Charlie.

Still, it wasnt a decision she made lightly.

I had that moment of, Is this the right thing to do? Handt said.

Early study results from Sarepta had shown the companys gene therapy could produce levels of miniature dystrophin markedly higher than previously reported in trials of other Duchenne medicines well beyond the amount that researchers think will alter the disease.

Yet data have been more mixed as to whether those protein levels translate to functional benefits. In some cases, boys who would have been expected to decline on tests evaluating their ability to walk, stand and balance, havent yet, which some experts point to as evidence the treatment is working.

What we're seeing is stabilization of the disease that we've never been able to stabilize before, said CHOPs Brandsema, who is an investigator in multiple Duchenne gene therapy trials, including Sareptas. That is a tremendous achievement.

While Handt couldnt be sure Sareptas treatment would help, Charlies disease was certain to progress. What is our alternative? she said. The idea of doing nothing, when we had something, was not an option.

Still, the gene therapies being developed for Duchenne, including Sareptas, use trillions of copies of the viral shells that deliver dystrophin DNA into the body. Though the virus in question has been safely used in scores of gene therapy experiments, prominent researchers have warned higher doses administered intravenously might not be as benign.

Those alarms have some merit. Four children died in a study of a gene therapy for a different type of neuromuscular disease. And while most of the side effects so far associated with Duchenne gene therapy appear manageable with close monitoring and a short course of immune-suppressing drugs, some rare but serious events have caused concern.

One patient died in a trial of Pfizers Duchenne gene therapy in 2021. Solids research was stalled multiple times due to safety worries. Data to date suggests Sareptas gene therapy to be generally safe, but it, too, was linked to one case of serious muscle weakness that researchers believe to be a shared effect among microdystrophin gene therapies. The company has excluded patients with certain mutations from testing in response.

We have to be very aware that this is an irreversible decision when we do this. It's like transplanting an organ or doing surgery, said Brandsema. We cannot take it back once weve given it, and the reaction can be significant.

Susan and Chris Finazzo carry their children around Jungle Island in Miami, Florida, on Oct. 23, 2022.

Permission granted by Susan and Chris Finazzo

The Handt family in Weed Beach in Darien, Connecticut, when Charlie (far right) was 3 years old.

Permission granted by Jennifer Handt

Seven years ago, hundreds of patients and family members traveled to a Washington, D.C., suburb to testify in support of an emerging treatment for Duchenne.

The drug, known then as eteplirsen and also developed by Sarepta, was up for an accelerated approval. The FDA had gathered a panel of experts to review the evidence.

The data primarily came from a clinical trial of just 12 boys with Duchenne, and reviewers were skeptical. The treatment produced a tiny amount of dystrophin less than 1% of normal levels and it was very difficult to discern whether it had an effect.

However, parents, patients and doctors were convinced the drug worked. At the meeting, some chided FDA officials, drawing cheers from the audience. Although the panel ruled narrowly against eteplirsen that day, the agencys top drug evaluator, Janet Woodcock, overruled her own review team, concluding the dystrophin levels were reasonably likely to result in a benefit. Her decision was supported by Robert Califf, the FDA commissioner then and now.

Eteplirsens approval caused a rift within the agency. Multiple reviewers left afterwards. In emails made public following the decision, Woodcock was accused by other staff members of flouting agency norms, keeping unusually close ties with Sarepta and patient advocates, and deciding to approve before reviewers had completed their evaluation.

Outside of the FDA, the approval was viewed as an example of the growing pressure patient groups many of which receive some degree of funding from drug companies were putting on regulators.

That advisory committee meeting harmed relationships within the [Duchenne] community, with the FDA, and the perception of our community outside, PPMDs Furlong said.

Sarepta still hasnt completed a required trial to confirm whether eteplirsen, which is now sold as Exondys 51, actually changes the diseases course.

According to Ingram, the companys CEO, the post-marketing study requested by the FDA wont directly answer that question, only whether higher doses might be more beneficial. He pointed instead to real-world evidence presented at a recent medical meeting, as well as a study showing dystrophin levels as low as 0.5% of normal are associated with milder disease. Neither type of data is as conclusive as results from a placebo-controlled trial.

In the meantime, Sarepta has become one of biotechs most valuable companies, currently worth about $12 billion. It followed a similar blueprint as Exondys 51 to bring two more drugs to market for different subsets of Duchenne patients, and began investing in gene therapy.

In my view, we wouldnt have [the gene therapy] today without Exondys 51s approval, he said. Its clear the FDA did the right thing.

Peter Marks, director of the Food and Drug Administrations Center for Biologics Evaluation and Research, testifies during a hearing in Washington, D.C., on March 18, 2021.

Susan Walsh/Pool/AP

In March, Peter Marks, head of an FDA office that reviews new drugs, stood before more than 1,000 researchers, patient advocates and doctors to give a speech on gene therapy.

Marks spoke of the agencys urgency to speed development of gene therapies for rare and life-threatening diseases, and the tools the FDA had to help. Among those was the accelerated approval pathway, which has been criticized in the years following Exondys clearance and only used once before for a gene therapy.

Marks acknowledged the criticism. Some see speedy approvals as a shortcut, he said. But we cant be so careful about our approvals under accelerated approval that we prevent potentially life-saving therapies from getting to market in a timely manner, he added.

The comments were notable given the venue. Marks was speaking at the yearly meeting of the Muscular Dystrophy Association, a large nonprofit group that supports research into neuromuscular diseases like Duchenne.

The talk was days after the FDA had scheduled an advisory meeting to review Sareptas accelerated approval application a meeting, Stat News subsequently reported, that Marks called after agency staff appeared ready to reject the treatment. Sarepta had previously said a meeting wasnt expected.

The conflicting news jarred the patient community, as advisory committees add an element of risk to the review process.

It made people step back a little bit, said Debra Miller, head of the advocacy group CureDuchenne, adding that theres a real feeling people need to band together to show the FDA we're behind this.

We all feel there's a really good chance that the therapy is going to be approved, Miller said.

Still, the tension highlights the risk Sarepta took by seeking an accelerated approval in the first place.

Sareptas headquarters are seen in Cambridge, Massachusetts in this undated photo.

Permission granted by Sarepta Therapeutics

The decision to file early, rather than wait for the results of the companys ongoing Phase 3 trial, was made after a lot of contemplation within the company, according to Ingram.

One factor was time. If Sarepta waited, at least one more year would pass before the gene therapy could possibly become available. In the life of a Duchenne kid, thats a monumentally long time, he said.

Ingram also pointed to the totality of the evidence Sarepta has already compiled. The treatments design is based on decades of research on the dystrophin genes of Becker patients, he said. It has been tested in about 150 boys and is supported by biological data suggesting its working. Children in the studies are doing better than normally would be expected and the therapys benefit may grow with time, he added.

Other experts interviewed by BioPharma Dive were supportive of the data as well.

This looks like a highly beneficial drug with relative risks that can be managed, said Lotze, of Texas Childrens, who isnt involved in Sarepta's trials. I would hope, and somewhat expect, that a treatment like this might halt further progression of disease or markedly slow it.

Still, Sareptas closest competitor, Pfizer, chose to wait for results from a Phase 3 study before deciding whether to file an application for its gene therapy.

The reason, according to its development head of rare neurologic diseases, Dan Levy, is that its challenging to tease apart a drugs effect by comparing the performance of Duchenne patients to historical data.

The patients who join a clinical trial and the ones involved in the natural history studies that document disease trajectory could be different. There are also biases and confounding factors that can skew results of the primary test used to measure Duchennes progression.

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'The luckiest of the unlucky': A Duchenne gene therapy brings hope ... - BioPharma Dive

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Research identifies new cause of heart failure condition in children – EurekAlert

image:A heart muscle cell with mutations in the gene that makes the Rotatin protein (bottom) has disorganized muscle fibers (red) compared to healthy heart muscle cell (top). view more

Credit: Matthew Miyamoto

In an effort to determine the cause behind a rare condition that causes heart failure in children, University of Maryland School of Medicine (UMSOM) researchers have identified new gene mutations responsible for the disorder in an infant patient. They were then able to learn how the mutation works and used a drug to reverse its effects in heart muscle cells derived from stem cells from the patient.

The findings, published in late April inCirculation,suggest that treatments could be developed to manage the condition rather than requiring a heart transplant, which is the standard treatment for this condition in children.

Although much has been studied about heart failure in adults, there is still much to learn about the genetic causes of heart failure in infants,saidCharles Chaz Hong, MD, PhD,Melvin Sharoky, MD Professor of Medicine and Physiology, Director of Cardiology Research, and Co-Chief of Cardiovascular Medicine at UMSOM.Mutations in the gene we identified had been implicated in microcephaly in babies but not yet in human heart disease.

Infantile dilated cardiomyopathy is a common cause of heart failure responsible for about half of pediatric heart failure cases whose cause is most often unknown. Although relatively rare, occurring in about one in 200,000 births, infants with the condition have hearts that fail to contract as effectively, so they are not able to pump as much blood as they should.

This genetic mutation discovered by Dr. Hong and his colleagues was found to normally make a protein found in a cell structure, the centrosome, that functions as a tether for the cells skeleton and is best known for its role during cell division.

Without this protein, muscle cells in the heart were unable to organize themselves neatly and did not contract as well, which in turn affected the hearts pumping, the researchers theorized.

We originally dismissed our findings as artifacts that the cell division machinery would be involved in this kind of heart muscle dysfunction,said Dr. Hong.We thought that once the heart cells matured, this cell division machinery completely disappeared, but it turned out, it moves to a new location in the cell and takes on a new role in heart muscle function.

To identify this gene mutation responsible for infant heart failure, the researchers removed a sample of heart cells from the patients diseased heart after it was removed during a transplant. They then converted this heart tissue to stem cells, so they could grow more cells and study them in the lab. They determined that the patient had two different mutations of a gene, one from each parent, that normally encodes for the Rotatin protein.

When the researchers then conducted an experiment to remove this same protein from zebrafish hearts, these hearts developed with signs of heart failure. The researchers also looked at fruit fly hearts missing Rotatin and saw that the muscle cells in these hearts were disorganized and did not contract as well as they should, similar to what happens in infant hearts with the disorder.

This is the first human disease known to be caused by disrupting the transition in centrosome structure which normally occurs shortly after birth,said Matthew Miyamoto, the first co-author who worked on this project as a rising second-year medical student in Dr. Hongs laboratory. The researchers then used the drug C19 that was known to organize centrosomes in developing heart muscle cells derived from the patient with infantile dilated cardiomyopathy. The drug restored organization of the developing heart muscle cells grown in a dish from the patients stem cells and their ability to contract.

Because centrosomes play such a fundamental role in heart muscle development, specifically cell replication, structure, and function, a better understanding of this tissue-specific programmed process will be highly relevant to future cardiac regenerative therapy efforts,said UMSOM Dean,Mark T. Gladwin, MD, who is also Vice President for Medical Affairs, University of Maryland, Baltimore (UMB), and the John Z. and Akiko K. Bowers Distinguished Professor.

Dr. Hong added,It is only through collaborations between cardiologists, medical student trainees, and laboratory researchers that allowed this biomedical discovery which we hope will one day translate to medical treatments for children with this condition.

Patrice Desvigne-Nickens, MD,a medical officer in the Heart Failure and Arrhythmias Branch in the Division of Cardiovascular Sciences at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, agreed.This study makes an important contribution toward understanding the biological underpinnings of infantile dilated cardiomyopathy and its relationship to heart failure,she said.We look forward to future studies to clarify and confirm these findings in an effort to improve heart failure outcomes.

This study was funded by grants from the NHLBI (R01HL135129), the Maryland Stem Cell Research Fund (HP-00089001), and an AOA Carolyn L. Kuckein Student Research Fellowship.

The authors have filed a pending patent on using C19 to treat infantile dilated cardiomyopathy. In accordance with UMB policy, the authors have disclosed their interest in the patent, and the university is managing this relationship to ensure objectivity in the research.

DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

About the University of Maryland School of Medicine

Now in its third century, the University of Maryland School of Medicine was chartered in 1807 as the first public medical school in the United States.It continues today as one of the fastest growing, top-tier biomedical research enterprises in the world with 46 academic departments, centers, institutes, and programs, and a faculty of more than 3,000 physicians, scientists, and allied health professionals, including members of the National Academy of Medicineand the National Academy of Sciences, and a distinguished two-time winner of the Albert E. Lasker Award in Medical Research.With an operating budget of more than $1.3 billion, the School of Medicine works closely in partnership with the University of Maryland Medical Center and Medical System to provide research-intensive, academic, and clinically based care for nearly 2 million patients each year. The School of Medicine has nearly $600 million in extramural funding, with most of its academic departments highly ranked among all medical schools in the nation in research funding.As one of the seven professional schools that make up the University of Maryland, Baltimore campus, the School of Medicine has a total population of nearly 9,000 faculty and staff, including 2,500 students, trainees, residents, and fellows. The combined School of Medicine and Medical System (University of Maryland Medicine) has an annual budget of over $6 billion and an economic impact of nearly $20 billion on the state and local community. The School of Medicine, which ranks as the8thhighestamong public medical schools in research productivity (according to the Association of American Medical Colleges profile) is an innovator in translational medicine, with 606 active patents and 52 start-up companies.In the latestU.S. News & World Reportranking of the Best Medical Schools, published in 2021, the UM School of Medicine isranked #9among the 92 public medical schoolsin the U.S., and in the top 15 percent(#27) of all 192public and privateU.S. medical schools.The School of Medicine works locally, nationally, and globally, with research and treatment facilities in 36 countries around the world. Visitmedschool.umaryland.edu

Experimental study

Cells

Impaired Reorganization of Centrosome Structure Underlies Human Infantile Dilated Cardiomyopathy

27-Mar-2023

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Research identifies new cause of heart failure condition in children - EurekAlert

Posted in Gene Medicine | Comments Off on Research identifies new cause of heart failure condition in children – EurekAlert