Update on the treatment of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is the most severe childhood form of muscular dystrophy caused by mutations in the gene responsible for dystrophin production. There is no cure, and treatment is limited to glucocorticoids that prolong ambulation and drugs to treat the cardiomyopathy. Multiple treatment strategies are under investigation and have shown promise for Duchenne muscular dystrophy. Use of molecular-based therapies that replace or correct the missing or nonfunctional dystrophin protein has gained momentum. These strategies include gene replacement with adeno-associated virus, exon skipping with antisense oligonucleotides, and mutation suppression with compounds that "read through" stop codon mutations. Other strategies include cell therapy and surrogate gene products to compensate for the loss of dystrophin. All of these approaches are discussed in this review, with particular emphasis on the most recent advances made in each therapeutic discipline. The advantages of each approach and challenges in translation are outlined in detail. Individually or in combination, all of these therapeutic strategies hold great promise for treatment of this devastating childhood disease.

Figure 1. Current strategies to deliver larger dystrophin genes for DMD

The full-length dystrophin cDNA (~14kb) precludes the use of AAV using standard methods. Proof of principle studies using three different methods have now demonstrated feasibility for dystrophin replacement. (A) Mini and micro (μ) versions of dystrophin which have deletions in spectrin repeat regions and/or the C-terminus of the protein have shown improvement in pre-clinical studies. (B) A trans-splicing approach is a dual vector strategy in which the transgene cassette is divided in two whereby a splice donor (SD) site is added to the 5′ vector and a splice acceptor (SA) site is added to the 3′ vector. Upon co-delivery to muscle the vectors concatamerize and undergo splicing to generate a full-length transcript. YFMG (your favorite muscle gene). (C) A second dual vector strategy employs an overlap sequence that is shared by both vectors (*). Following delivery to muscle, homologous recombination between the two vectors occurs to generate full-length transcript.