Hemophilia B Gene Therapy with a High-Specific-Activity Factor IX Variant

作者：Lindsey A. George, Spencer K. Sullivan, Adam Giermasz, John E.J. Rasko, Benjamin J. Samelson‐Jones, Jonathan M. Ducore, Adam C. Cuker, LISA M. SULLIVAN, Suvankar Majumdar, Jerome M. Teitel, Catherine E. McGuinn, Margaret V. Ragni, Alvin Y. Luk, Daniel J. Hui, John Fraser Wright, Yifeng Chen, Yun Liu, Katie Wachtel, Angela Winters, Stefan Tiefenbacher, Valder R. Arruda, Johannes C.M. van der Loo, Olga A. Zelenaia, Daniel M. Takefman, Marcus E. Carr, Linda B. Couto, Xavier M. Anguela, Katherine A. High · 发表于：New England Journal of Medicine · 年份：2017 · DOI：10.1056/nejmoa1708538 · 被引用次数：773 · 研究领域：Hemophilia Treatment and Research、Virus-based gene therapy research、Blood Coagulation and Thrombosis Mechanisms

BACKGROUND: The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important goal in the treatment of hemophilia. METHODS: vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values. RESULTS: No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year [range, 0 to 48] before vector administration vs. 0.4 events per year [range, 0 to 4] after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram [range, 0 to 8090] before vector administration vs. 49.3 IU per kilogram [range, 0 to 376] after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels develop...