Alan Beggs, PhD, on Digging Dipper Into Unexpected Toxicities With Neuromuscular Gene Therapy


The director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital discussed investigations into liver toxicity and deaths after AT132 gene therapy.

“The mechanism of toxicity has been unique and different from other gene therapy trials and illustrates the fact that X-linked myotubular myopathy (MTM) has a unique disease pathophysiology and that led to this particular risk, so this was a real disease specific problem... as it turns out patients with MTM had unrecognized liver abnormalities.”

While gene therapies may be establishing themselves as a mode of treatment in disease fields including neuromuscular disease, there is much to learn more about toxicities that patients may experience when receiving these disease modifying therapies.

Alan Beggs, PhD, Sir Edwin & Lady Manton Professor of Pediatrics, and director, Manton Center for Orphan Disease Research, and core director, Molecular Genetics Core, Intellectual and Developmental Disabilities Research Center (IDDRC), Boston Children’s Hospital, chaired a session at the 2024 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 3-6, in Orlando, Florida that focused on the road to developing a gene therapy for treating X-linked myotubular myopathy (MTM).

Clinical investigations into gene therapy for MTM were spearheaded by Audentes, then acquired by Astellas, and the AT132 gene therapy program. AT132 showed significant improvements in neuromuscular and respiratory function, but unexpected levels of liver toxicity leading to the deaths of 4 trial participants, a clinical hold, and stalled research.

Click here to view more coverage of the 2024 MDA Conference.

1. Beggs A, Buj-Bello A, Childers C, Dowling J, Gray J. Development of Gene Therapy for Rare and Ultra-Rare Neuromuscular Disease. Presented at: 2024 MDA Clinical and Scientific Conference; March 3-6; Orlando, FL.
2. Astellas reports update to September 1 announcement on the ASPIRO clinical trial of AT132 in patients with X-linked myotubular myopathy. News release. Astellas Pharma. September 14, 2021.
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