LB: Exploring Immune Management Strategies in Reducing Anti-AAV9 Preimmunity in Mice: Implications for Redosing Therapeutic Strategies in Gene Therapy


Translational Research

Poster Number: T430


Madhurima Saha, PhD, University of Florida, Radhika Bhake, MS, University of Florida, Craig Meyers, BS, University of Florida, Barry J Byrne, MD, PhD, University of Florida, Manuela Corti, PT, PhD, University of Florida

Introduction: Adeno-associated virus serotype 9 (AAV9) emerges as a promising gene therapy vector, known for its efficient genetic material delivery and minimal immune response. Nevertheless, the hurdle of preexisting immunity to AAV vectors hinders the effectiveness of gene therapy. This study delves into the impact of immune management strategies to alleviate the preexisting anti-AAV9 immune response in wild-type (WT) mice.
Methods: Exploring diverse immune management approaches involved exposing WT mice to AAV9 empty capsids, inducing a targeted immune response against AAV9. Establishing a state of preimmunity, a measured low dose (50 μg) of empty capsids was administered to incite the anti-AAV9 response. Immunomodulatory drugs, such as Sirolimus, anti-CD20 antibody, VELCADE, and VYVGART, were chosen and administered individually or in combination. Sirolimus, a rapamycin inhibitor, anti-CD20 antibody blocking B cell formation; VELCADE, a proteasome inhibitor, and VYVGART, a human Immunoglobulin G1 (IgG1) antibody fragment with high binding affinity to the neonatal Fc receptor, operated by competing with IgG for receptor binding, thereby reducing IgG circulation. Administration occurred during days 21-22, intraperitoneally or via oral gavage ROA, and therapeutic vectors (uDys9 and GAA) were introduced on day 70. The efficacy of each regimen in modulating the therapeutic anti-AAV9 response was assessed through AAV9-ELISA assay, GAA enzymatic assay, and microdystrophin expression.
Results: The study revealed significantly diminished levels of anti-AAV9 immunity in mice treated with Sirolimus, anti-CD20 antibody, VELCADE, and VYVGART, in contrast to control groups without immune management. Additionally, modest increases in transgene expression were observed in mice subjected to immunomodulation strategies.
Conclusion: These immune management strategies effectively reduce anti-AAV9 immunity in mice, showing promise in overcoming immunity challenges in AAV gene therapy. This progress broadens the possibilities for using these strategies in people who have encountered problems with preexisting AAV immunity, prompting additional investigation in clinical settings.