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

TLDR

Hemophilia B, an X‑linked disorder, is ideally suited for gene therapy, though immune‑mediated clearance of AAV‑transduced hepatocytes remains a concern that can be mitigated with short‑course glucocorticoids. The study investigated whether a single peripheral‑vein infusion of a serotype‑8 pseudotyped, self‑complementary AAV vector expressing codon‑optimized human FIX could treat severe hemophilia B. Six patients were sequentially assigned to high, intermediate, or low vector dose cohorts, received a single infusion without immunosuppression, and were followed 6–16 months to assess AAV‑mediated FIX expression. The treatment produced FIX expression of 2–11 % of normal, allowing four of six patients to discontinue prophylaxis without bleeding, while the two high‑dose patients experienced transient, glucocorticoid‑responsive liver enzyme elevations. The study was funded by the Medical Research Council and others and registered under ClinicalTrials.gov NCT00979238.

Abstract

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.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.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.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.).