Key result
Direct CNS administration of AAV gene therapies elicits milder immune responses and fewer adverse events compared to systemic injection, which demonstrates more robust immune stimulation.
Why the study?
Clinical trials of CNS-directed AAV gene therapy show contrasting immune responses and toxicities depending on whether administration is direct or systemic, warranting further exploration.
Does direct CNS delivery of AAV gene therapy alter immune responses compared to systemic delivery in patients with neurological disorders?
Does direct CNS delivery of AAV gene therapy alter immune responses compared to systemic delivery in patients with neurological disorders?
Direct CNS administration of AAV gene therapy may offer a safer immune profile with fewer off-target toxicities compared to systemic administration.
Immune monitoring remains essential in CNS AAV trials; leaves open optimal vector strategies for neurological disorders.
Adeno-associated virus (AAV) mediated gene therapy is a leading gene delivery platform with potential to transform the landscape of treatment for neurological disorders. While AAV is deemed non-immunogenic compared to other viral vectors, adverse immune reactions have been observed in the clinic, raising concerns. As the central nervous system (CNS) has a tightly regulated immune system, characterized by a degree of tolerance, it has been considered a unique target for AAV gene therapy. AAV vectors have shown promising results for the treatment of several CNS disorders including Spinal Muscular Atrophy, Giant Axonal Neuropathy, Amyotrophic Lateral Sclerosis, Tay Sachs Disease, Parkinson's Disease, and others, demonstrating safety and success. The Food and Drug Administration (FDA) approval of Zolgensma and European Medicines Agency (EMA) approval of Upstaza, for Spinal Muscular Atrophy (SMA) and Aromatic l-amino acid decarboxylase deficiency (AADC) respectively, represent this success, all while highlighting significant differences in immune responses to AAV, particularly with regards to therapeutic administration route. AAV therapies like Upstaza that are injected directly into the immune-specialized brain have been characterized by mild immune response profiles and minor adverse events, whereas therapies like Zolgensma that are injected systemically demonstrate more robust immune stimulation and off-target toxicities. Despite these contrasting parallels, these therapeutics and others in the clinic have demonstrated clinical benefit for patients, warranting further exploration of immune responses to CNS-directed AAV clinical trials. Thus, in this review, we discuss effects of different routes of AAV administration on eliciting local and peripheral immune responses specifically observed in CNS-targeted trials.
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Harkins et al. (2024) conducted a review in Neurological disorders. Central nervous system directed adeno-associated virus gene therapy vs. Systemic administration was evaluated on Local and peripheral immune responses. Direct CNS administration of AAV gene therapies elicits milder immune responses and fewer adverse events compared to systemic injection, which demonstrates more robust immune stimulation.
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