Muscular Dystrophy Association (MDA) has invested over $125 M in the development of gene therapy for neuromuscular disorders (NMD) over the past 20 years. As a lead initiator of progress in this important field of medicine and to help ensure continued progress towards therapies for patients, MDA organized a dedicated summit in January 2022 to address emerging challenges in safely delivering adeno-associated virus (AAV) mediated gene therapies with a focus on their application in NMD. In this meeting, chaired by Carsten Bönnemann (NINDS, NIH) and Barry Byrne (University of Florida), academic and industry experts and stakeholders convened to openly discuss adverse events linked to clinical trials, as well as other challenges emerging in preclinical studies associated with difficulties in the translation of AAV-mediated gene therapies.

BACKGROUND

Gene therapy using various serotypes of adeno associated viral (AAV) vectors for neuromuscular disorders (NMD) has advanced considerably in the last decade, with onasemnogene abeparvovec-xioi (Zolgensma®) having achieved regulatory approval in the United States and Europe [1]. There are currently five different AAV mediated clinical trials in patients for Duchenne muscular dystrophy [2], as well as trials underway for limb girdle muscular dystrophies, a congenital myopathy (MTM1)[3], Pompe disease [4], Danon disease [5], giant axonal neuropathy [6] and ALS [7], with many more in advanced preclinical stages. These trials highlight specific challenges associated with gene therapy for NMDs and related toxicities brought upon by these unique challenges. A thorough understanding of both determinants of efficacy as well as potential drivers of toxicity and risk will help the entire field adjust and advance carefully by proactively addressing potential toxicities to fully realize the translational potential of gene therapy for patients with NMDs.