Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Dec 8;2017(1):587-594.
doi: 10.1182/asheducation-2017.1.587.

Hemophilia gene therapy comes of age

Lindsey A George  1   2
Affiliations
Review

Hemophilia gene therapy comes of age

Lindsey A George. Hematology Am Soc Hematol Educ Program. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: The author has consulted for Pfizer.

Figures

Figure 1.
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.
Figure 2.
Peripheral administration of rAAV vector for liver-directed gene transfer for HA or HB.
See this image and copyright information in PMC

References

    1. Nathwani AC, Tuddenham EG, Rangarajan S, et al. . Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357-2365. - PMC - PubMed
    1. Nathwani AC, Reiss UM, Tuddenham EG, et al. . Long-term safety and efficacy of factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371(21):1994-2004. - PMC - PubMed
    1. Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J Med. 2001;344(23):1773-1779. - PubMed
    1. Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: progress and challenges. Nat Rev Genet. 2011;12(5):341-355. - PubMed
    1. Ohmori T, Mizukami H, Ozawa K, Sakata Y, Nishimura S. New approaches to gene and cell therapy for hemophilia. J Thromb Haemost. 2015;13(suppl 1):S133-S142. - PubMed