Review of cardiac safety in onasemnogene abeparvovec gene replacement therapy: translation from preclinical to clinical findings.
Deepa H ChandRui SunKarim A DiabDamien KennyFrancis Fonyuy TukovPublished in: Gene therapy (2023)
Human gene replacement 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 clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. 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. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.
Keyphrases
- left ventricular
- high dose
- clinical trial
- end stage renal disease
- replacement therapy
- knee osteoarthritis
- machine learning
- stem cells
- endothelial cells
- ejection fraction
- metabolic syndrome
- heart failure
- gene expression
- peritoneal dialysis
- mesenchymal stem cells
- type diabetes
- drinking water
- intensive care unit
- physical activity
- skeletal muscle
- cardiovascular events
- dna methylation
- copy number
- randomized controlled trial
- patient reported
- cell therapy
- electronic health record
- transcription factor
- public health
- smoking cessation
- acute kidney injury
- adipose tissue
- double blind
- risk factors
- prognostic factors
- low dose
- septic shock