Re-administration of AAV vectors by masking with host albumin: A Goldilocks hypothesis.

Strategies to administer AAV vectors safely and effectively to subjects with pre-existing antibodies are needed because of the high prevalence of wild-type AAV infection and increasing use of AAV-based products. Capsid antibodies block transduction, are cross-reactive between serotypes, 1 Kruzik A. Fetahagic D. Hartlieb B. Dorn S. Koppensteiner H. Horling F.M. Scheiflinger F. Reipert B.M. de la Rosa M. Prevalence of anti adeno-associated virus immune responses in international cohorts of healthy donors. Mol. Ther. Methods Clin. Dev. 2019; 14: 126-133 Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar and recipients of AAV vectors generate high-titer antibodies that are durable for years. 2 George L.A. Ragni M.V. Rasko J.E.J. Raffini L.J. Samelson-Jones B.J. Ozelo M. Hazbon M. Runowski A.R. Wellman J.A. Wachtel K. et al. Long-term follow-up of the first in human intravascular delivery of AAV for gene transfer: AAV2-hFIX16 for severe hemophilia B. Mol. Ther. 2020; 28: 2073-2082 Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar Immune complexes formed by antibody binding to AAV have been implicated in activation of the complement cascade 3 Zaiss A.K. Cotter M.J. White L.R. Clark S.A. Wong N.C.W. Holers V.M. Bartlett J.S. Muruve D.A. Complement is an essential component of the immune response to adeno-associated virus vectors. J. Virol. 2008; 82: 2727-2740 Crossref PubMed Scopus (100) Google Scholar associated with serious adverse events in high-dose clinical trials. Strategies to overcome this problem include discovery or creation of novel, immunologically distinct capsids 4 Bartel M. Schaffer D. Büning H. Enhancing the clinical potential of AAV vectors by capsid engineering to evade pre-existing immunity. Front. Microbiol. 2011; 2: 204https://doi.org/10.3389/fmicb.2011.00204 Crossref PubMed Scopus (79) Google Scholar that have the potential to increase the number of subjects eligible for a first-time treatment but will themselves induce high-titer antibodies that preclude AAV vector re-administration. Removal of AAV antibodies in subjects before vector administration by plasmapheresis, in vivo enzymatic digestion of total IgG, and prevention of antibody formation by immune suppression are promising approaches 5 Schulz M. Levy D.I. Petropoulos C.J. Bashirians G. Winburn I. Mahn M. Somanathan S. Cheng S.H. Byrne B.J. Binding and neutralizing anti-AAV antibodies: detection and implications for rAAV-mediated gene therapy. Mol. Ther. 2023; 31: 616-630 Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar but may not achieve sufficient antibody reduction and pose additional risks. Solving the antibody problem is key to maximize AAV gene therapy safety, efficacy, and wide utilization, including enablement of re-dosing to maintain the benefit achieved after an initial systemic dose that delivers therapeutic genes to liver or neuro-muscular cells but that fades with time or pediatric patient growth.