The sponsor of this clinical study, Audentes Therapeutics (which was acquired by Japan’s Astellas Pharma in 2019), had generated impressive efficacy studies in a canine model of MTM2 and conducted nonhuman primate (NHP) safety studies before advancing into the clinic. 3 The initial cohort of six pediatric MTM patients dosed at 1× 1014 genome copies (GC)/kg also showed encouraging results. However, all three patients administered a threefold higher dose (ie, 3× 1014 GC/kg) experienced severe hepatotoxicity, which has proven lethal in two of these subjects.

The success of the adeno-associated virus (AAV)-based product Zolgensma, approved in 2019 for the treatment of infants with spinal muscular atrophy (SMA) type 1, supported the safety and efficacy of infusing up to 1× 1014 GC/kg of vector into infants. 4 However, potentially doselimiting toxicities have been observed in some of the subjects who participated in gene therapy trials of Duchenne muscular dystrophy (DMD) using similarly high doses of AAV (Solid Bio, Sarepta, and Pfizer). 5 Some subjects from the SMA and three DMD trials developed an acute but transient decline in platelets, which required treatment in a few cases. Some of these trial subjects also developed reversible and asymptomatic liver damage, which in most cases was mild. However, two subjects in the Solid Bio trial and one subject in the Pfizer trial developed anemia due to hemolysis and renal failure, consistent with complement disorders associated with hemolytic–uremic syndrome. Several subjects in both DMD trials presented laboratory evidence of complement activation. Two patients with more severe renal failure required dialysis. Fortunately, all subjects recovered. In early 2018, one of us (JMW) reported in this journal severe toxicity in NHPs infused with high doses of