Adeno-associated viral vectors for the treatment of hemophilia

Abstract

Gene transfer studies for the treatment of hemophilia began more than two decades ago. A large body of pre-clinical work evaluated a variety of vectors and target tissues, but by the start of the new millennium it became evident that adeno-associated viral (AAV)-mediated gene transfer to the liver held great promise as a therapeutic tool. The transition to the clinical arena uncovered a number of unforeseen challenges, mainly in the form of a human-specific immune response against the vector that poses a significant limitation in the application of this technology. While the full nature of this response has not been elucidated, long-term expression of therapeutic levels of factor IX is already a reality for a small number of patients. Extending this success to a greater number of hemophilia B patients remains a major goal of the field, as well as translating this strategy to clinical therapy for hemophilia A. This review summarizes the progress of AAV-mediated gene therapy for the hemophilias, along with its upcoming prospects and challenges.

Figure 1.

Potential limitations in AAV therapy. (A) All viral sequences except the ITRs are replaced by an expression cassette, with a maximum capacity of around 4.7 kb. (B) Thus far, the AAV-based hemophilia trials have targeted either the muscle or the liver. Pre-existing anti-AAV neutralizing antibodies, even at modest titers, are able to prevent successful transduction after vector administration through the circulation. As a consequence, as many as 40% of adult hemophilia patients may be ineligible to participate in liver-directed AAV trials. (C) Once within the cell nucleus, the majority of AAV genomes are stabilized predominantly in an episomal form, which makes them susceptible to dilution if the cell divides. Episomes will integrate at a very low frequency and thus the potential risk of insertional mutagenesis exists. The capsid proteins presented on the cell surface may also flag the transduced cells for destruction. (D) Finally, a humoral immune response against the transgene product, the AAV capsid or both may be mounted.