Emerging genetic therapies to treat Duchenne muscular dystrophy

Abstract

Purpose of review: Duchenne muscular dystrophy is a progressive muscle degenerative disease caused by dystrophin mutations. The purpose of this review is to highlight two emerging therapies designed to repair the primary genetic defect, called 'exon skipping' and 'nonsense codon suppression'.

Recent findings: A drug, PTC124, was identified that suppresses nonsense codon translation termination. PTC124 can lead to restoration of some dystrophin expression in human Duchenne muscular dystrophy muscles with mutations resulting in premature stops. Two drugs developed for exon skipping, PRO051 and AVI-4658, result in the exclusion of exon 51 from mature mRNA. They can restore the translational reading frame to dystrophin transcripts from patients with a particular subset of dystrophin gene deletions and lead to some restoration of dystrophin expression in affected boys' muscle in vivo. Both approaches have concluded phase I trials with no serious adverse events.

Summary: These novel therapies that act to correct the primary genetic defect of dystrophin deficiency are among the first generation of therapies tailored to correct specific mutations in humans. Thus, they represent paradigm forming approaches to personalized medicine with the potential to lead to life changing treatment for those affected by Duchenne muscular dystrophy.

Figure 1. Therapeutic approaches to treat the primary defect in Duchenne muscular dystrophy

(a) Schematic representation of the dystrophin–glycoprotein and utrophin–glycoprotein complexes (DGC and UGC, respectively) composed of dystrophin or utrophin, sarcoglycans (α, β, γ, δ-subunits; yellow), dystroglycans (α-subunit and β-subunit; red), and sarcospan (SSPN, green). In DMD, mutations in dystrophin result in loss of the entire DGC and sarcolemmal damage. Improvements in dystrophic pathology can be accomplished by several mechanisms, including upregulation of compensatory proteins, treatment of muscle with poloxamer compounds, and enhanced α-dystroglycan glycosylation, which improves muscle cell attachment to the extracellular matrix through mechanisms involving the UGC. Many compensatory proteins have been identified and only a subset of these is illustrated. (b) Suppression of premature termination is an emerging therapy that attempts to bypass mutations in dystrophin that give rise to premature stop codons. Treatment of muscle with PTC124 results in the generation of full-length dystrophin protein with only one amino acid substitution at the site of the PTC (indicated in blue). (c) Therapeutic exon skipping utilizes antisense oligonucleotides that direct removal of exons containing nonsense or frame-shift mutations. In the example provided, a deletion mutation (exon 50; orange) alters the reading frame in the mRNA so that exon 49 (green) is spliced to exon 51 (purple). These splicing events result in a premature stop codon (TGA) within exon 51 and produce a truncated dystrophin protein that is nonfunctional and rapidly degraded. Oligonucleotides (PRO051) have been engineered to induce the spliceosome to skip this exon during RNA processing so that exon 49 is spliced directly to exon 52 (blue). The resultant mRNA encodes a truncated, but functional dystrophin protein lacking a small portion of the rod domain while maintaining the N-terminal and C-terminal regions important for protein interactions with actin (N-terminal dystrophin) and β-dystroglycan (C-terminal dystrophin).