What are the most common side effects associated with AAV-based gene therapy and how often do they occur?

There are two types of immune responses: innate and adaptive. Most adverse events in gene therapy studies have been linked to adaptive immune responses. Adaptative/Cellular Immune Response (Hepatotoxicity) happens at week 1-12 after the vector administration.

Immune-mediated liver toxicities can be encountered when an AAV vector is administered systemically. The presentation of the symptoms is normally: transaminase elevations (ALT most pronounced), decline in transgene-protein expression, IFN- ELISPOT to AAV capsid peptides. It occurs 1 week post vector administration, with a second peak (higher) at 1 month, concurrent with steroid wean or discontinuation. In the Zolgensma clinical trial participants, the vast majority (90%) had elevation in AST and ALT, but importantly, none had elevations of bilirubin more than 2x ULN, though all these recipients were on prophylactic steroids. Notably, only a small minority had very high elevations in liver enzymes.