Development of AAV vectors for the therapy of autoimmune and inflammatory diseases

Abstract

Adeno-associated virus (AAV) has been used as a gene delivery vehicle in over 60 human trials as a therapy for neurological, blood, lung, inflammatory, and muscle disorders. In these cases, the AAV vector has demonstrated both safety and efficacy; therapeutic transgene expression was observed in humans for greater than 5 years without associated side effects. Within the past decade, great progress has been achieved in AAV vector optimization for enhanced and targeted tissue transduction. Such advancements manifest at two levels, capsid and genome optimization, and include the characterization of new serotypes, rational and random capsid engineering, and the application of self-complementary, and split vector AAV genomes. These optimizations have allowed, not only enhanced and specific tissue transduction, but also the ability to evade the humoral response to the capsid and the delivery of payloads twice the packaging capacity. However, a recent clinical trial has put into question the immunogenicity of the AAV capsid in humans suggesting that transduced cells are often targeted by cytotoxic T cells, thus limiting the approaches efficacy in vivo. These advancements and limitations will be introduced and discussed with a focus on AAV’s utility for treating auto-immune disorders including preclinical and clinical trials.