Review of cardiac safety in onasemnogene abeparvovec gene therapy: translation from preclinical to clinical findings

Deepa Chand, Rui Sun,Karim Diab,Damien Kenny, Francis Funyuy Tukov

Research Square (Research Square)(2022)

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摘要
Abstract Human gene therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and all clinical sources following intravenous OA administration through 23 November 2021. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4–7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. SMA in itself, has been associated with cardiac events. Healthcare professionals should use medical judgement when assessing cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.
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onasemnogene abeparvovec onasemnogene therapy,cardiac safety,onasemnogene therapy
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