A U.S. Food and Drug Administration advisory panel has recommended against the approval of Sarepta's eteplirsen, a drug intended to treat Duchenne muscular dystrophy (DMD). Two other experimental DMD drugs have already been rejected. The recommendation came despite the emotional testimony of children who had apparently seen improvements due to the experimental treatment. Representative Mike Fitzpatrick, R-Pa. also spoke on behalf of a constituent with DMD. However, concerns were raised about the small sample size of the trial:
"I am very sorry to say that approval of eteplirsen based on today's data would set a dangerously low bar for all drugs in the future," said Gottschalk, a senior fellow at the National Center for Health Research, a nonprofit in Washington, D.C. "Treatments for rare diseases can be proven on small samples, but not based on 12 patients in a poorly designed study with ambiguous results. These boys and their families deserve better."
The problem, FDA scientists said earlier in the day, is that, due to its small size and design, the study Sarepta submitted to the agency cannot prove that eteplirsen deserves credit for the boys' ability to remain on their feet. Although the company says dozens more boys are now taking the drug, its case with the FDA rests on only the study involving the 12 boys in the orange t-shirts. Except for the first 24 weeks, all of the boys in that study have been taking the drug. With no long-term placebo group, Sarepta chose to compare them to untreated boys from a registry of DMD patients. These types of studies tend to have more favorable results than studies that randomly assign participants to the active treatment or a placebo, Dr. Robert Temple, deputy director of the FDA office that evaluates nervous system drugs, told the advisory committee.
The advisory panel's 7-3 recommendation (with three abstentions) is not the final word on eteplirsen, but the FDA generally follows such recommendations. Sarepta's shares plummeted on the news.
A new and non-viral approach to CRISPR has been used to treat Duchenne muscular dystrophy in mice:
A new version of the CRISPR-Cas9 gene-editing technology called CRISPR-Gold has successfully restored the correct sequence of the dystrophin gene in a mouse model of Duchenne muscular dystrophy (DMD), a new study revealed.
Researchers found that an injection of CRISPR-Gold into DMD mice led to an 18-times-higher correction rate and a two-fold increase in a strength and agility test compared to control groups, according to a press release.
The study, "Nanoparticle delivery of Cas9 ribonucleoprotein and donor DNA in vivo induces homology-directed DNA repair," [DOI: 10.1038/s41551-017-0137-2] [DX] was published in the journal Nature Biomedical Engineering.
[...] Unfortunately, methods of delivering the components of this system, which include an RNA molecule called a guide RNA, a protein called the Cas9 nuclease, and the correct DNA sequence to replace the mutation (via donor DNA), have not been fully developed for human use. A primary technique used to deliver the components of this system relies on viruses, but this technique is plagued by complications and unwanted side effects.
In response, researchers at the University of California, Berkeley have developed a new approach called CRISPR-Gold, which used gold nanoparticles to deliver the components of this system in a mouse model of DMD. This method works by using gold nanoparticles to coat a modified DNA molecule that binds the donor DNA, which in turn is bound to Cas9 and the guide RNA.
This entire system is then coated by a polymer that will interact with a cell membrane and allow entry into a cell. Then, the components of the system are released into the cell as the coat breaks apart upon entry. The guide RNA, the Cas9 nuclease, and the donor DNA can then make their way into the nucleus and correct the mutation.
Also at TheScientist.
Previously: FDA Panel Recommends Rejection of Duchenne Muscular Dystrophy Treatment
Marathon Pharmaceuticals is Part of the Problem
Marathon Pharmaceuticals Cashes Out on Regulatory Loopholes
What is a Muscle Protein Doing in the Brain?
Fighting fire with fire, researchers working with dogs have fixed a genetic glitch that causes Duchenne muscular dystrophy (DMD) by further damaging the DNA. The unusual approach, using the genome editor CRISPR, allowed a mutated gene to again make a key muscle protein. The feat—achieved for the first time in a large animal—raises hopes that such genetic surgery could one day prevent or treat this crippling and deadly disease in people. An estimated 300,000 boys around the world are currently affected by DMD.
The study monitored just four dogs for less than 2 months; more animal experiments must be done to show safety and efficacy before human trials can begin. Even so, "I can't help but feel tremendously excited," says Jennifer Doudna of the University of California, Berkeley, who heard the results last week at a CRISPR meeting she helped organize. "This is really an indication of where the field is heading, to deliver gene-edited molecules to the tissues that need them and have a therapeutic benefit. Obviously, we're not there yet, but that's the dream."
[...] The study offers little evidence that dogs regained muscle function, however, and that, coupled with the short duration of the study and the small number of animals studied, left some scientists less enthusiastic. One researcher in the tight-knit DMD field who asked not to be named wonders whether the study was rushed to help draw investment in Exonics Therapeutics, a Boston-based company Olson launched last year to develop the potential treatment.
[...] Another challenge was to alter billions of muscle cells throughout a living animal. So the team enlisted a helper: a harmless adeno-associated virus that preferentially infects skeletal muscle and heart tissue. Two 1-month-old dogs received intramuscular injections of the virus, engineered to carry CRISPR's molecular components. Six weeks later, those muscles were making dystrophin again. Those results led the researchers to give an intravenous infusion to two more dogs, also 1 month old, to see whether the CRISPR-carrying viruses could add the genome editor to muscles throughout the body. By 8 weeks, Olson told the meeting, dystrophin levels climbed to relatively high levels in several muscles, reaching 58% of normal in the diaphragm and 92% in the heart. But because the dogs were euthanized, Olson could show little evidence that they had avoided DMD symptoms, save for a dramatic video of a treated dog walking and jumping normally.
Also at Science News.
Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy (DOI: 10.1126/science.aau1549) (DX)
More about Duchenne muscular dystrophy at Wikipedia.
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