Selected Grantee Publications

Engineered IgM and IgG Cleaving Enzymes for Mitigating Antibody Neutralization and Complement Activation in AAV Gene Transfer

Smith et al., Molecular Therapy. 2024.

https://www.sciencedirect.com/science/article/pii/S1525001624003058?via%3Dihub=

Recombinant adeno-associated viral (AAV) vectors have emerged as the leading platform for therapeutic gene transfer, but systemic dosing of AAV vectors poses potential risk of adverse side effects, including complement activation triggered by anti-capsid immunity. In this study, investigators discovered an IgM cleaving enzyme (IceM) that degrades human IgM, a key trigger in the anti-AAV immune cascade. They engineered a fusion enzyme (IceMG) with dual proteolytic activity against human IgM and IgG. Antisera from animals treated with IceMG show decreased ability to neutralize AAV and activate complement. These studies have implications for improving the safety of AAV gene therapies and offer broader applications, including for organ transplantation and autoimmune diseases. Supported by ORIP (P51OD011107, U42OD027094), NHLBI, and NIAID.