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Audentes Therapeutics’ experimental exon skipping gene therapy may safely and effectively increase dystrophin levels and stabilize muscle function in Duchenne muscular dystrophy (DMD) patients with exon duplications, according to six-month data from the first two treated boys in a Phase 1/2 clinical trial.
These preliminary data, representing the first evidence of full-length dystrophin protein production following gene therapy, also supported further testing of the treatment in younger patients and at higher doses.
Early findings were presented in the poster “Expression of apparent full-length dystrophin in skeletal muscle in a first-inhuman gene therapy trial using the scAAV9.U7-ACCA vector,” at the 2021 MDA Virtual Clinical and Scientific Conference running March 15–18.
DMD is caused by mutations in the DMD gene, which provides the instructions to produce a key protein for muscle health called dystrophin.
While the most common DMD-causing mutations involve the deletion of one or more exons — sections of genetic information needed to make proteins — exon duplications account for nearly 11% of cases of DMD or other conditions characterized by dystrophin deficiency. Of these, a duplication of exon 2 is the most frequent.
Exons’ genetic information is transcribed into an intermediate molecule called messenger RNA (mRNA) that is used to guide protein production. Exons are translated and, much like with a puzzle, pieced together in the mRNA molecule.
Exon loss or duplication often breaks the ability of nearby exons to link together properly, impairing the production of a working dystrophin protein.
Exon skipping therapies are designed to skip a specific exon in the DMD gene’s mRNA, so the remaining exons do fit together. This allows for the production of a working, but usually shorter, version of dystrophin.
Skipping of exon 2 has considerable potential to treat people with exon 2 duplications. Skipping only one of the duplicated exons results in the normal production of a full-length dystrophin protein, while skipping both exons leads to the generation of a highly functional version of dystrophin.
DMD patients with exon 2 deletions are mildly affected, being largely asymptomatic.
Researchers at the Nationwide Children’s Hospital, in Ohio, developed an exon skipping therapy that uses a modified and harmless virus, called scAAV9.U7-ACCA, to deliver the genetic sequence of four molecules designed to force exon 2 skipping in the DMD gene’s mRNA. The one-time therapy is given directly into the bloodstream.
Previous studies in a mouse model with DMD exon 2 duplication showed the therapy effectively promoted the skipping of one or both exon 2s, and resulted in dose-dependent increases in dystrophin levels and muscle function improvement. Data also allowed the determination of the minimally effective dose to be used in patients.
Further preclinical research found no clinically significant toxicity in mice and non-human primates given the therapy.
These results supported the launch of a first clinical trial (NCT04240314) in boys with DMD.
This Phase 1/2 study is evaluating the safety and preliminary effectiveness of the investigational gene therapy (at a dose of 3×1013 vector genomes per kilogram) in up to three boys, ages 6 months to 13 years, with a duplication of exon 2 in the DMD gene. Each will be followed for two years.
The trial is being conducted by the Nationwide Children’s Hospital, in collaboration with Audentes.
Newly presented data concerned the first two treated boys in the trial. At dosing, one boy was 8.9 years old, and the other 13.7 years old.
An examination six months later showed both boys tolerated the treatment well, with temporary abdominal pain, nausea, and vomiting, and no reports of serious adverse events. The levels of liver enzymes rose briefly in the first two months — suggestive of liver toxicity and a common side effect of gene therapy — in both patients.
Levels of creatine kinase, a marker of muscle damage, were markedly lower, and functional outcome measures remained stable over time in both boys.
Muscle biopsies showed an increase in the levels of apparently full-length dystrophin protein at six months in both patients, but the younger boy had the highest raise — more than twice that of the older patient. The researchers said this may reflect a higher degree of muscle fiber damage in the older boy, possibly challenging viral entry in these fibers.
These findings “represent the first therapeutic [production] of apparent full-length dystrophin in a human gene therapy trial,” the researchers wrote, adding that they support “further clinical investigation in younger subjects and dose escalation.”
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