ASPIRO gene replacement therapy trial with resamirigene bilparvovec in XLMTM: pathologic findings in four deceased study participants

Background: X-linked myotubular myopathy (XLMTM) is caused by mutations in the MTM1 gene, leading to absent or dysfunctional myotubularin, respiratory failure and profound muscle weakness at birth, and early death.

Objective: We report the pathologic findings of 4 deceased XLMTM patients who received investigational MTM1 gene replacement therapy.

Methods: ASPIRO (NCT03199469) is an open-label, phase 1/2/3 randomized trial in which young boys with genetically confirmed XLMTM and chronic ventilator dependence received resamirigene bilparvovec (AT132), a single intravenous dose of adeno-associated viral (AAV) vector delivering human MTM1.

Results: Three of 17 participants in the higher dose (3.5x1014 vg/kg) and 1 of 7 participants in the lower dose (1.3x1014 vg/kg) cohort died. All 4 deceased participants had ongoing hepatobiliary cholestasis with decompensated liver disease at death. Immediate causes of death included sepsis and gastrointestinal hemorrhage. Two serial liver biopsies obtained from 1 participant demonstrated progression to liver fibrosis over the course of ~7 months. All 4 participants had histological similarities. This progressive, cholestatic disease was associated with a previously unrecognized cholestatic tendency, exposure to AT132 with mechanism of cholestatic disease exacerbation not understood, and evidence of decreased expression of bile salt export protein (BSEP) in liver tissue. Retrospective analyses of preclinical mouse and canine XLMTM models and healthy non-human primates treated with AAV8 gene transfer did not reveal evidence of cholestatic disease.

Conclusions: Deaths were attributable to AT132-triggered severe exacerbation of cholestatic liver disease; factors that would help predict this susceptibility remain under investigation while the ASPIRO study is currently on hold. aASPIRO Pathology Study Group: James J. Dowling, Benedikt Schoser, Marta Margeta, Hui Meng, Amanda M. Hopp, Laura Wozniak, A. Reghan Foley, Dimah N. Saade, David E. Kleiner, Esra Dikoglu, Christine Jones, Osorio Lopes Abath Neto, Astrid Blaschek, Eberhard Lurz, Susanna Mueller, Nitin R Wadhwani, Saeed Mohammad, Catherine A Chapin, Robyn C. Reed, Evelyn Hsu, Suyash Prasad, Salvador Rico, Michael Murtagh, Nathan Bachtell.

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023