Adenovirus-Associated Virus Vector–Mediated Gene Transfer in Hemophilia B

Amit C. Nathwani(Cancer Institute (WIA)), Edward G. D. Tuddenham, Savita Rangarajan(Basingstoke and North Hampshire Hospital), Cecilia Rosales(University College London), Jenny McIntosh(University College London), David C. Linch(University College London), Pratima Chowdary, Anne Riddell, Arnulfo Pie, Chris F. Harrington, James O’Beirne(Education Trust), Keith Smith(NHS Blood and Transplant), John Pasi(Queen Mary University of London), Bertil Glader(St. Jude Children's Research Hospital), Pradip K. Rustagi(Stanford University), Catherine Y. Ng(St. Jude Children's Research Hospital), Mark A. Kay(Stanford University), Junfang Zhou(St. Jude Children's Research Hospital), Yunyu Spence(St. Jude Children's Research Hospital), Christopher L. Morton(St. Jude Children's Research Hospital), James A. Allay, John B. Coleman, Susan Sleep, John M. Cunningham(University of Chicago), Deo Kumar Srivastava(St. Jude Children's Research Hospital), Etiena Basner‐Tschakarjan(Children's Hospital of Philadelphia), Federico Mingozzi(Children's Hospital of Philadelphia), Katherine A. High(Children's Hospital of Philadelphia), John T. Gray(St. Jude Children's Research Hospital), Ulrike M. Reiss(St. Jude Children's Research Hospital), Arthur W. Nienhuis(St. Jude Children's Research Hospital), Andrew M. Davidoff(St. Jude Children's Research Hospital)
New England Journal of Medicine
December 10, 2011
10.1056/nejmoa1108046
Cited by 1,835Open Access
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Abstract

BACKGROUND: Hemophilia B, an X-linked disorder, is ideally suited for gene therapy. We investigated the use of a new gene therapy in patients with the disorder. METHODS: We infused a single dose of a serotype-8-pseudotyped, self-complementary adenovirus-associated virus (AAV) vector expressing a codon-optimized human factor IX (FIX) transgene (scAAV2/8-LP1-hFIXco) in a peripheral vein in six patients with severe hemophilia B (FIX activity, <1% of normal values). Study participants were enrolled sequentially in one of three cohorts (given a high, intermediate, or low dose of vector), with two participants in each group. Vector was administered without immunosuppressive therapy, and participants were followed for 6 to 16 months. RESULTS: AAV-mediated expression of FIX at 2 to 11% of normal levels was observed in all participants. Four of the six discontinued FIX prophylaxis and remained free of spontaneous hemorrhage; in the other two, the interval between prophylactic injections was increased. Of the two participants who received the high dose of vector, one had a transient, asymptomatic elevation of serum aminotransferase levels, which was associated with the detection of AAV8-capsid-specific T cells in the peripheral blood; the other had a slight increase in liver-enzyme levels, the cause of which was less clear. Each of these two participants received a short course of glucocorticoid therapy, which rapidly normalized aminotransferase levels and maintained FIX levels in the range of 3 to 11% of normal values. CONCLUSIONS: Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression. (Funded by the Medical Research Council and others; ClinicalTrials.gov number, NCT00979238.).

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