Immunomodulation in Administration of rAAV: Preclinical and Clinical Adjuvant Pharmacotherapies

Abstract

Recombinant adeno-associated virus (rAAV) has attracted a significant research focus for delivering genetic therapies to target cells. This non-enveloped virus has been trialed in many clinical-stage therapeutic strategies but important obstacle in clinical translation is the activation of both innate and adaptive immune response to the protein capsid, vector genome and transgene product. In addition, the normal population has pre-existing neutralizing antibodies against wild-type AAV, and cross-reactivity is observed between different rAAV serotypes. While extent of response can be influenced by dosing, administration route and target organ(s), these pose concerns over reduction or complete loss of efficacy, options for re-administration, and other unwanted immunological sequalae such as local tissue damage. To reduce said immunological risks, patients are excluded if they harbor anti-AAV antibodies or have received gene therapy previously. Studies have incorporated immunomodulating or suppressive regimens to block cellular and humoral immune responses such as systemic corticosteroids pre- and post-administration of Luxturna® and Zolgensma®, the two rAAV products with licensed regulatory approval in Europe and the United States. In this review, we will introduce the current pharmacological strategies to immunosuppress or immunomodulate the host immune response to rAAV gene therapy.

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.…”

“…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 39 . Other agents that affect both T and B cells responses and are used with rAAV therapies are sirolimus and mycophenolate mofetil.…”

“…The other agent that has been used is rituximab, a monoclonal antibody targeting CD20 positive pre‐B and mature B cells, limiting antibody production and epitope presentation to helper T cells 41 . All of the mentioned agents have been used in various rAAV clinical trials, and several combination therapies are being trialled in preclinical models 39 …”

Therapeutic Application of Extracellular Vesicles-Capsulated Adeno-Associated Virus Vector via nSMase2/Smpd3, Satellite, and Immune Cells in Duchenne Muscular Dystrophy

“…Therefore, as one of the novel gene therapy strategies, a drug delivery system for the AAV-encapsulating EV, which contains the AAV vector within the EV, was reported to be useful in the intervention of various target tissues in some diseases [189][190][191][192][193][194][195][196][197][198][199][200]. Furthermore, the effectiveness of gene therapy with AAV vectors is greatly affected by neutralizing antibodies [81,[201][202][203]. Therefore, the induction of immune tolerance to AAV vectors has become an important issue for efficient and safe gene transduction.…”

Risk Mitigation of Immunogenicity: A Key to Personalized Retinal Gene Therapy

“…In recent clinical trials, glucocorticoids have been the most widely used anti-inflammatory drugs. Representatives of this family include prednisone, prednisolone, and dexamethasone, which were used pre-operation (for 1 to 3 days) as well as post-surgery (for longer periods of time, up to three weeks), taken orally or applied locally, in multiple clinical trials as well as in conjunction with EMA- and FDA-approved Luxturna [ 131 , 132 ].…”