Unraveling the Complex Story of Immune Responses to AAV Vectors Trial After Trial

Abstract

Over the past decade, vectors derived from adeno-associated virus (AAV) have established themselves as a powerful tool for in vivo gene transfer, allowing long-lasting and safe transgene expression in a variety of human tissues. Nevertheless, clinical trials demonstrated how B and T cell immune responses directed against the AAV capsid, likely arising after natural infection with wild-type AAV, might potentially impact gene transfer safety and efficacy in patients. Seroprevalence studies have evidenced that most individuals carry anti-AAV neutralizing antibodies that can inhibit recombinant AAV transduction of target cells following in vivo administration of vector particles. Likewise, liver- and muscle-directed clinical trials have shown that capsid-reactive memory CD8+ T cells could be reactivated and expanded upon presentation of capsid-derived antigens on transduced cells, potentially leading to loss of transgene expression and immune-mediated toxicities. In celebration of the 25th anniversary of the European Society of Gene and Cell Therapy, this review article summarizes progress made during the past decade in understanding and modulating AAV vector immunogenicity. While the knowledge generated has contributed to yield impressive clinical results, several important questions remain unanswered, making the study of immune responses to AAV a priority for the field of in vivo transfer.

Astrocyte-selective AAV-ADAMTS4 gene therapy combined with hindlimb rehabilitation promotes functional recovery after spinal cord injury

“…Following in vitro experiments, we determined whether injections of the AAV-dYFP vector had any effects on astrogliosis or caused behavioural deficits in a spinal cord contusion model. This study was carried out over 4 weeks because beyond this time point any effect to behaviour or astrogliosis could reflect dYFP transgene-related effects rather than a response to the viral vector particles (Vandamme et al, 2017). As observed in vitro, AAV-dYFP did not affect astrogliosis in comparison to non-injected animals ( Fig.…”

Long term AAV2/9-mediated silencing of PMP22 prevents CMT1A disease in rats and validates skin biomarkers as treatment outcome measure

“…Over the past decade AAV-based therapies have shown numerous successes from proof of concept to clinical trials in genetic diseases [17,27]. These studies have also identified off-targets transduction and humoral immune response against the vector as the two main serious obstacles that hinder successful AAV-based therapies in patients [39,61]. We therefore evaluated the biodistribution of AAV2/9 vector throughout the rat body 3 months after injection in sciatic nerves.…”

AAV-Mediated Progranulin Delivery to a Mouse Model of Progranulin Deficiency Causes T Cell-Mediated Toxicity

“…[26][27][28] To transduce the CNS, AAV can be delivered to brain parenchyma or cerebrospinal fluid (CSF), with therapeutic benefit in preclinical models of both gain-and loss-of-function diseases. [29][30][31][32][33][34] In contrast to peripheral administration, 35,36 numerous studies have shown minimal innate or adaptive immune response to AAV-mediated gene delivery in the CNS.…”