B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study

Abstract

Gene therapy strategies for congenital myopathies may require repeat administration of adeno-associated viral (AAV) vectors in response to several limitations inherent to the clinical design: 1) administration of doses below therapeutic efficacy in patients enrolled in early phase clinical trials; 2) progressive reduction of the therapeutic gene expression over time as a result of increasing muscle mass in patients treated at a young age; and 3) a possibly faster depletion of pathogenic myofibers in this patient population. Immune responses triggered by the first vector administration, and to subsequent ones, represent a major obstacle for successful gene transfer in young patient population. Anti-capsid and anti-transgene product related humoral and cell-mediated responses have been previously observed in all preclinical models and human subjects who received gene therapy or ERT treatment for congenital myopathies. Immune responses may result in reduced efficacy of the gene transfer over time and/or may preclude for the possibility of re-administration of the same vector. This study presents a case of Pompe patient dosed with an AAV1-GAA vector after receiving Rituximab and Sirolimus to modulate the immune responses. A key finding of this single subject case report is the observation that B-cell ablation with rituximab prior to AAV vector exposure results in non-responsiveness to both capsid and transgene, therefore allowing the possibility of repeat administration in the future. This observation is significant for future gene therapy studies and establishes a clinically relevant approach to blocking immune responses to AAV vectors.

Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion

“…Although CAM variants can be reengineered further, if warranted, our structureguided approach complements other methods to circumvent preexisting humoral immunity in prospective patients that are currently being explored in preclinical studies (5). One promising approach involves the use of immunosuppressive agents that can mitigate NAb generation after vector dosing (25). Although the side effects of these agents are well documented, this approach may help develop treatment regimens that require vector redosing.…”

Copackaged AAV9 Vectors Promote Simultaneous Immune Tolerance and Phenotypic Correction of Pompe Disease

“…11,[42][43][44][45][46][47] In addition, we and others have described the capabilities of AAV-mediated expression of GAA to elicit detrimental immune responses against the transgene. 1,50,55 To address this complication for improved systemic outcomes, we pursued the use of a liver-specific promoter (apolipoprotein Ehepatocyte locus control region-human alpha-1 antitrypsin promoter [LSP]) to drive expression of human codon-optimized GAA (coGAA) for induction of GAA-specific T regs capable of dampening a systemic immune response against GAA. [56][57][58] The construct was packaged in two separate serotypes: AAV8 and AAV9.…”

“…48,49 It is noteworthy that clinical management of the immune response was necessary during the course of this clinical trial to prevent antitransgene immunity as ERT was maintained for ethics considerations. 50 Therefore, developing immune tolerance induction strategies to be combined with gene therapies is at the forefront of investigation for Pompe disease and similar diseases that undergo protein replacement therapies. 20 In this work, we provide evidence that both disease-related functional deficits and immune tolerance can be simultaneously addressed using AAV9-mediated GAA expression.…”

Obstacles and future of gene therapy for hemophilia

“…Similarly, intensive immunosuppression with rituximab, anti-thymoglobulin, methylprednisolone, mycophenlate mofetil and tacrolimus was only modestly and temporarily able to limit anti-AAV NAb formation in NHPs after an initial dose of liver-directed AAV gene therapy [20]. In contrast, extended immunosuppression with rituximab, rapamycin and IVIG limited anti-AAV antibody formation in a human subject after AAV1-based gene therapy for Pompe disease [21]. These mixed results are, at least partially, due to the distinct conditions of each of the aforementioned reports.…”