Gene Therapy for Duchenne Muscular Dystrophy

Abstract

Abstract Duchenne muscular dystrophy is a severe muscle wasting disorder caused by lack of functional dystrophin, due to reading‐frame disrupting mutations in the DMD gene. There is no cure, but several genetic therapeutic approaches aiming to delay disease progression by restoring, manipulating or replacing the DMD gene are under investigation in (pre)clinical settings. The antisense‐mediated exon skipping approach, which restores the disrupted reading frame allowing synthesis of partly functional dystrophin proteins is closest to clinical application. The first trials with viral vectors to deliver minidystrophin genes and compounds to force readthrough of premature stop codons by the translation machinery have also been undertaken, whereas other approaches, like genome editing, are still in the early development phase. Despite some remaining hurdles that have to be overcome, lessons learned can be used to catalyse the development of potential therapies. Key Concepts: Duchenne muscular dystrophy (DMD) is caused by reading‐frame disrupting mutations in the DMD gene, resulting in premature termination of dystrophin synthesis. Inframe mutations allow synthesis of shorter, but partly functional dystrophin proteins, resulting in the milder Becker muscular dystrophy (BMD) phenotype. Antisense oligonucleotide‐mediated exon skipping aims to restore the reading frame enabling synthesis of BMD‐like dystrophins, thereby converting the severe DMD into the milder BMD disease. Gene replacement therapy (replacing the dysfunctional dystrophin cDNA) is hampered by the size and complexity of the DMD gene and dystrophin cDNA. AAV vectors have a limited loading capacity of ∼4.5 kb, requiring the use of mini‐, or microdystrophin genes that encode only the most crucial functional domains. Ataluren can be used to force the translational machinery to ignore premature stop codons enabling synthesis of intact dystrophin. Endonuclease‐mediated generation of double‐strand breaks can be used to correct the genetic mutation or restore the reading frame. Many therapeutic approaches have progressed to clinical trials.