The progress of AAV-mediated gene therapy in neuromuscular disorders

ABSTRACT

Introduction: The well-defined genetic causes and monogenetic nature of many neuromuscular disorders, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), present gene therapy as a prominent therapeutic approach. The novel variants of adeno-associated virus (AAV) can achieve satisfactory transduction efficiency of exogenous genes through the central nervous system and body-wide in skeletal muscle.

Areas covered: In this review, we summarize the strategies of AAV gene therapy that are currently under preclinical and clinical evaluation for the treatment of degenerative neuromuscular disorders, with a focus on diseases such as DMD and SMA. In addition to gene replacement strategy, we provide an overview of other approaches such as AAV-mediated RNA therapy and gene editing in the treatment of muscular dystrophies.

Expert opinion: AAV gene therapy has achieved striking therapeutic efficacy in clinical trials in infants with SMA. Promising results have also come from the preclinical studies in small and large animal models of DMD and several clinical trials are now on the way. This strategy shows great potential as a therapy for various neuromuscular disorders. Further studies are still required to confirm its long-term safety and improve the efficacy.

KEYWORDS:

• Adeno-associated virus
• gene therapy
• gene editing
• muscular dystrophy
• neuromuscular disorders
• RNA therapy
• spinal muscular atrophy

Article highlights

• Recombinant adeno-associated virus (rAAV) vectors are efficient in transducing exogenous genes body-wide following systemic delivery, with target organs including skeletal muscles, cardiac muscles, and motor neurons.

• AAV gene therapy represents a promising approach for treating Duchenne/Becker muscular dystrophy (DMD/BMD), spinal muscular atrophy (SMA), and myotubular myopathy.

• The successful clinical trial of scAAV9-SMN (AVXS-101) shows striking efficacy and it is among the most promising therapeutic approaches for the treatment of infants with type I SMA.

• In addition to gene replacement, other approaches such as AAV-mediated RNA therapy and gene editing have also shown potential in the treatment of neuromuscular diseases.

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Declaration of interest

S. Aguti and A. Malerba are supported by Muscular Dystrophy UK. H. Zhou is supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre (GOSH BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre (GOSH BRC).