• Amit C Nathwani, Edward G D Tuddenham, Savita Rangarajan, Cecilia Rosales, Jenny McIntosh, David C Linch, Pratima Chowdary, Anne Riddell, Arnulfo Jaquilmac Pie, Chris Harrington, James O'Beirne, Keith Smith, John Pasi, Bertil Glader, Pradip Rustagi, Catherine Y C Ng, Mark A Kay, Junfang Zhou, Yunyu Spence, Christopher L Morton, James Allay, John Coleman, Susan Sleep, John M Cunningham, Deokumar Srivastava, Etiena Basner-Tschakarjan, Federico Mingozzi, Katherine A High, John T Gray, Ulrike M Reiss, Arthur W Nienhuis, and Andrew M Davidoff.
• Department of Haematology, University College London Cancer Institute, London, United Kingdom. a.nathwani@ucl.ac.uk
• N. Engl. J. Med. 2011 Dec 22; 365 (25): 2357-65.

BackgroundHemophilia 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.MethodsWe 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.ResultsAAV-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.ConclusionsPeripheral-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.).

18 keywords...

hide…