Bioengineered coagulation factor VIII enables long-term correction of murine hemophilia A following liver-directed adeno-associated viral vector delivery

• Type of Material: Article
• Authors: Harrison C Brown, Emory University; J Fraser Wright, The Children's Hospital of Philadelphia; Shangzhen Zhou, The Children's Hospital of Philadelphia; Jordan E Sheilds, Emory University; Harold Trent Spencer, Emory University; Christopher Doering, Emory University
• Language: English
• Date: 2014
• Publisher: Nature Publishing Group: Open Access Journals - Option B
• Publication Version: Final Published Version
• Copyright Statement: © 2014 American Society of Gene & Cell Therapy
• License: Creative Commons Attribution 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1038/mtm.2014.36
• Title of Journal or Parent Work: Molecular Therapy - Methods and Clinical Development
• ISSN: 2329-0501
• Volume: 1
• Start Page: 14036
• End Page: 14036
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health; 1 U54 HL112309-01 and 1 R01 HL092179-01A2 to C.B.D. and H.T.S., and T32GM008602 to H.C.B.
• Research Categories: Biology, Molecular; Health Sciences, Pharmacology; Health Sciences, Medicine and Surgery

Abstract

Clinical data support the feasibility and safety of adeno-associated viral (AAV) vectors in gene therapy applications. Despite several clinical trials of AAV-based gene transfer for hemophilia B, a unique set of obstacles impede the development of a similar approach for hemophilia A. These include (i) the size of the factor VIII (fVIII) transgene, (ii) humoral immune responses to fVIII, (iii) inefficient biosynthesis of human fVIII, and (iv) AAV vector immunity. Through bioengineering approaches, a novel fVIII molecule, designated ET3, was developed and shown to improve biosynthetic efficiency 10- to 100-fold. In this study, the utility of ET3 was assessed in the context of liver-directed, AAV-mediated gene transfer into hemophilia A mice. Due to the large size of the expression cassette, AAV-ET3 genomes packaged into viral particles as partial genome fragments. Despite this potential limitation, a single peripheral vein administration of AAV-ET3 into immune-competent hemophilia A mice resulted in correction of the fVIII deficiency at lower vector doses than previously reported for similarly oversized AAV-fVIII vectors. Therefore, ET3 appears to improve vector potency and mitigate at least one of the critical barriers to AAV-based clinical gene therapy for hemophilia A.