ADVM-053 / Adverum Biotech - LARVOL DELTA

In the presence of pre-existing anti-AAV immunity, systemic administration of low dose AAV triggers complement activation within minutes (ASGCT 2026) - "Methods Six African Green NHPs were intravenously administered AAVrh.10 vectors at two timepoints 42 days apart: four (2 males, 2 females) received AAVrh.10 expressing human C1 esterase inhibitor (AAVrh.10hC1EI; 1x1013 gc/kg) and two (1 male, 1 female) received an identical AAVrh.10 vector lacking a transgene cassette (AAVrh.10-Null; 1x1013 gc/kg)...Conclusion In summary, we have identified a new possible adverse event associated with systemic administration of a low dose of AAV in the setting of established anti-AAV antibodies evoking rapid, transient complement activation. The rapid onset and resolution of TCC elevation represents an early (within minutes) and narrow temporal window that may be overlooked in clinical monitoring protocols, highlighting the need for early complement monitoring within the first hour post-administration in human gene therapy trials to allow for timely detection and determination if there are any associated clinical consequences."

Atypical Hemolytic Uremic Syndrome • Gene Therapies • Hematological Disorders • Inflammation • Nephrology

Safety consequences on complement system integrity of systemic AAV-mediated C1 esterase inhibitor gene therapy for hereditary angioedema (ASGCT 2026) - "None of the NHPs showed abnormalities of the classical, alternative or lectin pathways. Conclusion We conclude that complement pathway functionality remained intact throughout the study at all time points assessed, indicating hC1EI expression from intravenous delivered AAVrh.10hC1EI gene therapy does not impair complement function, eliminating a theoretical safety concern for clinical translation of this potential treatment for HAE."

Clinical • Gene therapy • Cardiovascular • Complement-mediated Rare Disorders • Gene Therapies • Hereditary Angioedema • AVEN

Gene Therapy for C1 Esterase Inhibitor Deficiency in a Murine Model of Hereditary Angioedema. (PubMed, Allergy) - "A single treatment with AAVrh.10hC1EI has the potential to provide long term protection from angioedema attacks in affected individuals."

Journal • Preclinical • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema