ORLANDO, Florida—The rationale behind mechanisms of endogenous dystrophin restoration for the treatment of Duchenne muscular dystrophy (DMD) was introduced by Barry Byrne, MD, PhD, the associate chair of pediatrics and director of the Powell Gene Therapy Center at the University of Florida in Gainesville during the Exon Skipping and Readthrough Agents session at the CureDuchenne 2022 FUTURES National Conference.

During the session, Dr. Byrne covered the basics behind exon skipping and gene therapy. He compared the 2 approaches and talked about the challenges and opportunities that each one offers. He also talked about stop codon readthrough, a strategy that mitigates the effects of a mutation creating a premature stop codon in the coding sequence of the gene.

Dr. Bryne explained why each approach is mutation-specific and why they will not work for every patient. He described how the development of each exon-skipping drug, for example, was driven by the frequency of each mutation class among the patient population.

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Even gene therapy by gene addition is not totally mutation independent, he said. “There are some regions of the expressed protein that are absent in the subject that might be present in the vector, and those can create other immunological consequences.”

Read more about experimental therapies for DMD

Dr. Byrne also talked about adeno-associated virus-delivered exon skipping, which was discussed publicly for the first time a little more than a week ago at the American Society of Gene Therapy.

The approach was used to treat DMD caused by the duplication of exon 2, which affects around 1% of all patients with the disease. Here, instead of using gene therapy to insert a gene that codes for a smaller version of dystrophin protein, the viral vector introduces a noncoding gene that continually makes antisense RNA that targets exon 2 in the DMD gene. This way, cells can “ignore” at least one copy of exon 2 and make some full-length dystrophin protein.

The study was conducted at Nationwide Children’s Hospital in Columbus, Ohio and researchers reported that it led to the production of full-length dystrophin protein in 3 patients with DMD. This is the first time full-length dystrophin was produced in a patient with DMD as a result of a therapeutic intervention.

Dr. Bryne’s presentation was followed by short presentations and a discussion by representatives of industries working on these different strategies.  


Exon skipping and readthrough agents panel. Poster presented at: CureDuchenne 2022 FUTURES National Conference; May 27-29, 2022; Orlando, FL.