Preclinical models to assess the immunogenicity of AAV vectors.

Although gene transfer using adeno-associated virus (AAV) vectors has made tremendous progress in recent years, challenges remain due to vector-specific adaptive immune responses. Specifically, AAV-neutralizing antibodies reduce AAV-transduction rates, while CD8+ T cells directed to AAV capsid antigens cause rejection of AAV-transduced cells. This has been addressed clinically by excluding humans with pre-existing AAV-neutralizing antibodies from gene transfer trials or by using immunosuppression or reduced doses of vectors expressing improved transgene products to blunt or circumvent destructive T cell responses. Although these approaches have met with success for treatment of some diseases, most notably hemophilia B, they may not be suitable for others. Pre-clinical models are thus needed to test alternative options to sidestep pre-existing AAV-neutralizing antibodies, to prevent their induction following gene transfer and to block the detrimental effects of CD8+ T cells directed to AAV capsid antigens. This chapter describes some of the available, although not yet perfect, models that can assess immune responses to AAV gene transfer.