Neonatal Fc Receptor Inhibition Enables Adeno-Associated Virus Gene Therapy Despite Pre-Existing Humoral Immunity.

Advances in adeno-associated virus (AAV)-based gene therapy are transforming our ability to treat rare genetic disorders and address other unmet medical needs. However, the natural prevalence of anti-AAV neutralizing antibodies (NAbs) in humans currently limits the population who can benefit from AAV-based gene therapies. Neonatal Fc receptor (FcRn) plays an essential role in the long half-life of IgG, a key NAb. Researchers have developed several FcRn-inhibiting monoclonal antibodies to treat autoimmune diseases, as inhibiting the interaction between FcRn and IgG Fc can reduce circulating IgG levels to 20-30% of the baseline. We evaluated the utility of one such monoclonal antibody, M281, to reduce pre-existing NAb levels and to permit gene delivery to the liver and heart via systemic AAV gene therapy in mice and nonhuman primates. M281 successfully reduced NAb titers along with total IgG levels; it also enhanced gene delivery to the liver and other organs after intravenous administration of AAV in NAb-positive animals. These results indicate that mitigating pre-existing humoral immunity via disruption of the FcRn-IgG interaction may make AAV-based gene therapies effective in NAb-positive patients.

Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors.

Gene therapy using neurotropic adeno-associated virus vectors represents an emerging solution for genetic disorders affecting the central nervous system. The first approved central nervous system-targeting adeno-associated virus gene therapy, Zolgensma®, for treating spinal muscular atrophy is administered intravenously at high doses that cause liver-associated adverse events in 20%-30% of patients. Intrathecal routes of vector administration, such as the intra-cisterna magna route, provide efficient gene transduction to central nervous system cells while reducing off-target liver transduction. However, significant levels of liver transduction often occur upon intra-cisterna magna vector delivery in preclinical studies. Using vectors expressing monoclonal antibody transgenes, we examined whether passive transfer of adeno-associated virus-neutralizing antibodies as intravenous immunoglobulin before intrathecal adeno-associated virus delivery improved the safety of viral gene therapy targeting the central nervous system in mice and nonhuman primates. We used intracerebroventricular and intra-cisterna magna routes for vector administration to mice and nonhuman primates, respectively, and evaluated transgene expression and vector genome distribution. Our data indicate that pretreatment with intravenous immunoglobulin significantly reduced gene transduction to the liver and other peripheral organs but not to the central nervous system in both species. With further refinement, this method may improve the safety of adeno-associated virus-based, central nervous system-targeting gene therapies in clinical settings.

Erratum: Intravenous immunoglobulin prevents peripheral liver transduction of intrathecally delivered AAV vectors.

[This corrects the article DOI: 10.1016/j.omtm.2022.09.017.].