Background: Four sponsors have ongoing clinical trials to evaluate the safety and/or efficacy of investigational gene therapies for the treatment of Duchenne muscular dystrophy (DMD). All approaches use an adeno-associated virus, albeit of different serotypes, to deliver various versions of a shortened dystrophin transgene. SAEs characterized by muscle weakness with variable cardiac involvement occurred with a strikingly similar clinical presentation and time course in trials of several therapies. The sponsors collaborated to share relevant clinical and laboratory data from all trials with an international panel of experts in order to further the understanding of the SAEs, minimize their recurrence, and assess potential therapeutic and preventative strategies.
Summary of SAEs: Onset of symptoms, including leg and bulbar muscle weakness, occurred approximately 2-3 weeks following investigational gene therapy infusion. Severe respiratory muscle compromise occurred in some cases. When cardiac involvement occurred, increased cardiac troponin-I levels were observed. Following various immunosuppressive therapies, cardiac enzyme levels normalized and strength improved over the course of 3 months.
Potential mechanism: Given similar events across investigational products, the mechanism is unlikely to be related to the capsid or promoter type. Laboratory data suggest a T-cell mediated immune response to the transgene protein as the most likely mechanism. The SAEs occurred in patients having genomic deletions affecting N-terminal epitopes which are present in the transgene protein, likely resulting in a cross-reactive immunological material (CRIM)-negative setting. A plan for further investigation was outlined to comprehensively define the immune mechanism and associated risk factors.
Conclusions: An open collaboration among four sponsors of ongoing studies and multiple academic experts identified an anti-transgene mechanism and associated risk factors for observed SAEs, discussed mitigating strategies, and identified data to be collected prospectively. This collaborative approach and its conclusions may have implications to mitigate risks in gene therapy development programs beyond DMD.