Preexisting Neutralizing Antibodies against Different Adeno-Associated Virus Serotypes in Humans and Large Animal Models for Gene Therapy.

Gene therapy is a potential cure for several inherited retinal dystrophies, and adeno-associated virus (AAV) has emerged as a vector of choice for therapeutic gene delivery to the retina. However, prior exposure to AAVs can cause a humoral immune response resulting in the presence of antibodies in the serum, which can subsequently interfere with the AAV-mediated gene therapy. The antibodies bind specifically to a serotype but often display broad cross-reactivity. A subset of these antibodies called neutralizing antibodies (NABs) can render the AAV inactive, thereby reducing the efficacy of the therapy. The preexisting NAB levels against different serotypes vary by species, and these variations need to be considered while designing studies. Since large animals often serve as preclinical models to test gene therapies, in this review we compile studies reporting preexisting NABs against commonly used AAV serotypes in humans and large animal models and discuss strategies to deal with NABs.