Hemophilia gene therapy comes of age

Abstract

Concurrent with the development of recombinant factor replacement products, the characterization of the F9 and F8 genes over 3 decades ago allowed for the development of recombinant factor products and made the hemophilias a target disease for gene transfer. The progress of hemophilia gene therapy has been announced in 3 American Society of Hematology scientific plenary sessions, including the first "cure" in a large animal model of hemophilia B in 1998, first in human sustained vector-derived factor IX activity in 2011, and our clinical trial results reporting sustained vector-derived factor IX activity well into the mild or normal range in 2016. This progression to clinically meaningful success combined with numerous ongoing recombinant adeno-associated virus (rAAV)-mediated hemophilia gene transfer clinical trials suggest that the goal of gene therapy to alter the paradigm of hemophilia care may soon be realized. Although several novel therapeutics have recently emerged for hemophilia, gene therapy is unique in its potential for a one-time disease-altering, or even curative, treatment. This review will focus on the prior progress and current clinical trial investigation of rAAV-mediated gene transfer for hemophilia A and B.

Figure 1.

Hypothesis of the cellular immune response to hepatocytes after rAAV transduction. rAAV enters the hepatocyte by receptor-mediated endocytosis, wherein the vector genome, including the transgene, is released from the capsid (uncoating). Thereafter, the capsid is degraded in the cytosol, and capsid peptides are loaded onto major histocompatibility complex (MHC) class I on the surface of the transduced hepatocytes. Presentation of capsid peptides on MHC class I triggers a cellular immune response to the transduced hepatocytes, resulting in clearance of the hepatocyte.

Figure 2.

Peripheral administration of rAAV vector for liver-directed gene transfer for HA or HB.