Duchenne muscular dystrophy (MD), a common and serious form of childhood muscle wasting, typically arises from genomic deletions of one or more exons that disrupt the dystrophin reading-frame. Gene deletions that maintain the dystrophin reading-frame generally result in the milder Becker MD. Genotype:phenotype correlations clearly indicate that more than half the 79 dystrophin exons can be omitted from the mRNA without seriously compromising protein function. We have developed a splice intervention therapy using antisense oligonucleotides to specifically redirect dystrophin pre-mRNA processing. Targeted exon skipping can either re-frame a dystrophin mRNA corrupted by the loss of a frame-shifting exon or remove an exon containing a protein-truncating mutation.
Exondys 51, a morpholino oligomer designed to excise human dystrophin exon 51 from the mature mRNA, was granted accelerated approval by the US Food and Drug Administration. Relevant to about 10% of DMD mutations, Exondys 51 is the first dystrophin restoring drug, the first exon-skipping drug, and the first morpholino oligomer to be approved for clinical use.
Designing clinical trials to evaluate drugs for rare diseases is challenging, especially when patient numbers are small and disease progression is relatively slow. There was vigorous and heated discussion within and outside the FDA after the accelerated approval of Exondys 51, and these concerns will be discussed and addressed. Therapeutic alternative splicing strategies must be tailored to different dystrophin mutations and Phase 3 clinical trials have been initiated to evaluate skipping of two other dystrophin exons.
Since most human genes undergo some form of splicing during expression, therapeutic alternative splicing could be relevant to many other inherited and acquired conditions, especially if mutated exons were known to be dispensable. We are currently exploring splice intervention therapies for spinal muscular atrophy, cystic fibrosis. Marfan’s disease, Ehler-Danlos syndrome, adult-onset Pompe’s disease, Epidermolysis bullosa, amyotrophic lateral sclerosis and multiple sclerosis.