Translational importance of non-human primates for the study of the immune response in gene therapy procedures involving in vivo administration of rAAV vectors

In vivo gene therapies based on viral vectors, particularly recombinant adeno-associated viruses (rAAV), have become a promising approach for the treatment of various genetic diseases. However, the immune response against these vectors is still a major obstacle, affecting their efficacy and safety. This review examines the importance of non-human primates (NHPs) as translational models for the study of immune responses against rAAVs. After an overview of the characteristics of AAV vectors and the challenges posed by the translatability of animal models, we analyze the innate and adaptive immune responses to these vectors, highlighting the role of neutralizing antibodies and cytotoxic cells. We also discuss the severe adverse events observed in clinical trials, such as liver toxicity, thrombotic microangiopathy and neurotoxicity, and their correlation with preclinical studies on NHPs. Finally, we discuss strategies to improve the safety and efficacy of rAAV-based therapies, including immune modulation and optimization of preclinical models. All of these elements highlight the need to improve the translatability of preclinical results for better predictability of side effects and optimization of therapeutic protocols.