Immune Responses and Immunosuppressive Strategies for Adeno-Associated Virus-Based Gene Therapy for Treatment of Central Nervous System Disorders: Current Knowledge and Approaches

Figures

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  Figure 1.. Overview of the innate immune response to AAV vectors. (A) At the cell surface, AAV capsids can bind TLR2 that recruits MyD88 and leads to activation of NF-κB and subsequent expression of genes that encode inflammatory cytokines ①. Within the cell, vector genomes can be exposed during endosomal trafficking and recognized by TLRs. CpG-rich AAV DNA activates intracellular TLR9 and the subsequent expression of genes that encode inflammatory cytokines via MyD88 and NF-κB ②, whereas dsRNA induces the expression of type I interferon genes via TLR3 ③ or RIG-1/MDA5 ④. Pharmacotherapies that can inhibit these pathways are shown in red, including corticosteroids and hydroxychloroquine. (B) Complement is activated via the classical, lectin, or alternative pathways. All pathways converge at the point of C3 activation and cleavage of C3 into C3a and C3b fragments ①. Opsonization of AAV by C3b fragments leads to activation of macrophages and phagocytosis of opsonized AAV ②. C3b also activates C5 and leads to the formation of the MAC in AAV-infected cells ③. Created with BioRender.com. Diagram is based on data available at the time of article development. AAV, adeno-associated virus; C1,…

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  Figure 2.. Overview of the adaptive immune responses AAV vectors. AAV capsids and transgene-encoded proteins within a transduced dendritic cell can be degraded by the proteosome and the resulting peptides are presented on MHCs leading to activation and proliferation of CD4+ and CD8+ T cells ①. Activated T helper cells signal B cells to produce antibodies directed at the capsid or transgene-encoded protein ②. nAbs against the AAV capsid inhibit interactions of AAV with its cellular receptor to prevent binding and transduction ③. Effector CD8+ T cells recognize and bind to other AAV-transduced cells presenting capsid or transgene-encoded peptides on MHC I molecules and initiate the cytotoxic T cell response ④. Pharmacotherapies that can interfere with these pathways are shown in red and include calcineurin inhibitors (tacrolimus and cyclosporine), corticosteroids, rapamycin, MMF, and rituximab. Created with BioRender.com. Diagram is based on data available at the time of article development. Ab, antibody; CD, cluster of differentiation; IFN-γ, interferon gamma; IFN-γR, interferon gamma receptor; MHC, major histocompatibility complex; MMF, mycophenolate mofetil; mRNA, messenger ribonucleic…

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  Figure 3.. CNS routes of administration for AAV gene therapy and potential toxicities to monitor. Delivery of AAV gene therapy vectors to the CSF via ICV, ICM, or IT administration reduces the systemic exposure and severity of immune-mediated adverse events. Potential toxicities that should be monitored include TMA, hepatotoxicity, and dorsal root ganglion toxicity. Created with BioRender.com. CNS, central nervous system; CSF, cerebrospinal fluid; ICV, intracerebroventricular; ICM, intra-cisterna magna; IT, intrathecal; TMA, thrombotic microangiopathy.