Immune responses in gene therapy with adeno-associated virus (AAV) vectors have been the object of almost two decades of study. Although preclinical models helped to define and predict certain aspects of interactions between the vector and the host immune system, most of our current knowledge has come from clinical trials. These studies have allowed development of effective interventions for modulating immunotoxicities associated with vector administration, resulting in therapeutic advances. However, the road to full understanding and effective modulation of immune responses in gene therapy is still long; the determinants of the balance between tolerance and immunogenicity in AAV vector–mediated gene transfer are not fully understood, and effective solutions for overcoming preexisting neutralizing antibodies are still lacking. However, despite these challenges, the goal of reliably delivering effective gene-based treatments is now in sight.


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