Adenovirus-associated virus vector-mediated gene transfer in hemophilia B.
2357 - 2365
N Engl J Med
MetadataShow full item record
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.).
AuthorsNathwani, AC; Tuddenham, EGD; Rangarajan, S; Rosales, C; McIntosh, J; Linch, DC; Chowdary, P; Riddell, A; Pie, AJ; Harrington, C; O'Beirne, J; Smith, K; Pasi, J; Glader, B; Rustagi, P; Ng, CYC; Kay, MA; Zhou, J; Spence, Y; Morton, CL; Allay, J; Coleman, J; Sleep, S; Cunningham, JM; Srivastava, D; Basner-Tschakarjan, E; Mingozzi, F; High, KA; Gray, JT; Reiss, UM; Nienhuis, AW; Davidoff, AM
- College Publications