Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia

Abstract

Adeno-associated viral (AAV) vector gene therapy has shown promise as a possible cure for hemophilia. However, immune responses directed against AAV vectors remain a hurdle to the broader use of this gene transfer platform. Both innate and adaptive immune responses can affect the safety and efficacy of AAV vector–mediated gene transfer in humans. These immune responses may be triggered by the viral capsid, the vector’s nucleic acid payload, or other vector contaminants or excipients, or by the transgene product encoded by the vector itself. Various preclinical and clinical strategies have been explored to overcome the issues of AAV vector immunogenicity and transgene-related immune responses. Although results of these strategies are encouraging, more efficient approaches are needed to deliver safe, predictable, and durable outcomes for people with hemophilia. In addition to durability, long-term follow-up of gene therapy trial participants will allow us to address potential safety concerns related to vector integration. Herein, we describe the challenges with current methodologies to deliver optimal outcomes for people with hemophilia who choose to undergo AAV vector gene therapy and the potential opportunities to improve on the results.

DBS Screening for Glycogen Storage Disease Type 1a: Detection of c.648G>T Mutation in G6PC by Combination of Modified Competitive Oligonucleotide Priming-PCR and Melting Curve Analysis

“…This notwithstanding, in AAV-vector-mediated GRT, expression of a non-self-protein could trigger widespread immune response against the human transgene [ 26 , 27 ], which presents a fundamental challenge to gene therapy [ 22 ]. However, it was observed that AAV-based GRT in neonates, in the critical period of immunological development, could induce an immunological tolerance to the transgene product, improving the safety and tolerance of gene therapy [ 22 , 28 ].…”

Emerging concepts of miRNA therapeutics: from cells to clinic

“…An adeno-associated viral vector system is currently employed in a Phase II study on the treatment of Huntington's disease to permit the cellular delivery of the amiRNA drug AMT-130 (ClinicalTrials.gov identifier NCT04120493) [23][24][25]. Although viral delivery systems are unquestionably powerful tools to further cellular uptake and expression of miRNAs, various complications such as immunogenicity have been reported [63]. The outcome of clinical trials such as the one for amiRNA drug AMT-130 must be awaited before a further judgment can be drawn.…”

Gene therapy: Practical aspects of implementation

“…Several therapeutic interventions are being employed to overcome rAAV immunogenicity to improve the predictability and longevity of gene therapy. 38,39 The choice of therapeutic agents originates from Corticosteroids in the form of prednisone and prednisolone are the most commonly employed immune-modulatory agents. They demonstrate both anti-inflammatory and immunosuppressive properties with broad inhibitory effects on innate and adaptive cells by reducing the production of proinflammatory cytokines, chemokines, and T cells.…”

“…Several therapeutic interventions are being employed to overcome rAAV immunogenicity to improve the predictability and longevity of gene therapy 38,39 . The choice of therapeutic agents originates from their use in other autoimmune disorders or organ transplantation and trial and error.…”