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

Amit C. Nathwani, M.B., Ch.B., Ph.D., Edward G.D. Tuddenham, M.B., B.S., M.D., Savita Rangarajan, M.B., B.S., Cecilia Rosales, Ph.D., Jenny McIntosh, Ph.D., David C. Linch, M.B., B.Chir., Pratima Chowdary, M.B., B.S., Anne Riddell, B.Sc., Arnulfo Jaquilmac Pie, B.S.N., Chris Harrington, B.S.N., James O'Beirne, M.B., B.S., M.D., Keith Smith, M.Sc., John Pasi, M.D., Bertil Glader, M.D., Ph.D., Pradip Rustagi, M.D., Catherine Y.C. Ng, M.S., Mark A. Kay, M.D., Ph.D., Junfang Zhou, M.D., Yunyu Spence, Ph.D., Christopher L. Morton, B.S., James Allay, Ph.D., John Coleman, M.S., Susan Sleep, Ph.D., John M. Cunningham, M.D., Deokumar Srivastava, Ph.D., Etiena Basner-Tschakarjan, M.D., Federico Mingozzi, Ph.D., Katherine A. High, M.D., John T. Gray, Ph.D., Ulrike M. Reiss, M.D., Arthur W. Nienhuis, M.D., and Andrew M. Davidoff, M.D.

December 10, 2011 (10.1056/NEJMoa1108046)

Comments open through December 16, 2011

Abstract
Article
References
Comments (1): 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.
Full Text of Background...
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.
Full Text of Methods...
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.
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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.)
Full Text of Discussion...