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采用高特异性活性因子Ⅸ变体的血友病B基因疗法
Hemophilia B Gene Therapy with a High-Specific-Activity Factor Ⅸ Variant


Lindsey A. George ... 肿瘤 • 2017.12.07
NEJM 动画解读

凝血因子IX缺乏的基因疗法
相关阅读
• 第59届美国血液学会年会报告——良性血液病 • 因子Ⅸ缺乏型血友病的基因治疗 • AAV5-凝血因子Ⅷ转基因治疗重度血友病A

摘要


背景

在单次治疗干预后通过充分维持凝血因子水平预防出血,且不需要进一步的医疗干预,是血友病治疗的重要目标。

 

方法

我们给10名因子Ⅸ促凝活性为正常值2%或以下的男性血友病B患者输注由经生物工程改造的衣壳、肝特异性启动子和因子Ⅸ Padua(因子Ⅸ-R338L)转基因组成的单链腺相关病毒(AAV)载体,剂量为每千克体重5×1011个载体基因组。实验室检查结果、出血频率和Ⅸ因子浓缩物的用量在载体输注后进行前瞻性评估,并与基线值进行比较。

 

结果

载体输注期间或之后没有发生严重不良事件。在所有参与者中载体源性因子Ⅸ促凝活性得以维持,平均(±SD)稳态因子Ⅸ促凝活性为33.7%±18.5%(范围14%~81%)。所有参与者累计随访492周(个体参与者随访范围是28~78周),年出血率显著降低(输注载体前平均发生率11.1次/年[范围是0~48次/年] vs. 输注后0.4次/年[范围是0~4次/年;P=0.02),因子用量也显著减少(平均剂量,输注载体前2,908 IU/kg [范围是0~8,090IU/kg] vs. 输注后49.3 IU/kg [范围是0~376 IU/kg];P=0.004)。10名参与者中有8名没有使用凝血因子,有9名在载体给药后没有出血。两名参与者发生无症状的肝酶水平升高,并在泼尼松短期治疗后缓解。一名参与者在基线时有严重的晚期关节病,使用因子治疗出血,但总体而言因子用量比载体输注前减少91%。

 

结论

在接受相同载体剂量的10例血友病患者中,我们发现基因转移后因子Ⅸ促凝活性产生持续的、有治疗作用的表达。转基因源性因子Ⅸ的促凝活性可终止基线预防治疗,并且几乎消除了出血和凝血因子的使用(由Spark Therapeutics公司和辉瑞公司资助;在ClinicalTrials.gov注册号为NCT02484092)。





作者信息

Lindsey A. George, M.D., Spencer K. Sullivan, M.D., Adam Giermasz, M.D., Ph.D., John E.J. Rasko, M.B., B.S., Ph.D., Benjamin J. Samelson-Jones, M.D., Ph.D., Jonathan Ducore, M.D., M.P.H., Adam Cuker, M.D., Lisa M. Sullivan, M.D., Suvankar Majumdar, M.D., Jerome Teitel, M.D., Catherine E. McGuinn, M.D., Margaret V. Ragni, M.D., M.P.H., Alvin Y. Luk, Ph.D., Daniel Hui, Ph.D., J. Fraser Wright, Ph.D., Yifeng Chen, M.D., Yun Liu, Ph.D., Katie Wachtel, M.S., Angela Winters, M.P.H., Stefan Tiefenbacher, Ph.D., Valder R. Arruda, M.D., Ph.D., Johannes C.M. van der Loo, Ph.D., Olga Zelenaia, Ph.D., Daniel Takefman, Ph.D., Marcus E. Carr, M.D., Ph.D., Linda B. Couto, Ph.D., Xavier M. Anguela, Ph.D., and Katherine A. High, M.D.
From the Division of Hematology (L.A.G., B.J.S.-J., A.W., V.R.A.) and the Raymond G. Perelman Center for Cellular and Molecular Therapeutics (L.A.G., B.J.S.-J., A.W., V.R.A., J.C.M.L., O.Z.), Children’s Hospital of Philadelphia, the Departments of Pediatrics (L.A.G., B.J.S.-J., V.R.A.) and Medicine (A.C.), Perelman School of Medicine at the University of Pennsylvania, and Spark Therapeutics (A.Y.L., D.H., J.F.W., Y.C., Y.L., K.W., D.T., M.E.C., L.B.C., X.M.A., K.A.H.) — all in Philadelphia; the Department of Pediatrics, Mississippi Center for Advanced Medicine, Madison (S.K.S.), and the Departments of Pathology (L.M.S.) and Pediatrics (S.M.), University of Mississippi Medical School, Jackson; the Departments of Medicine (A.G.) and Pediatrics (J.D.), University of California–Davis Medical School, Sacramento; the Department of Medicine, Sydney Medical School, and the Gene and Stem Cell Therapy Program, Centenary Institute (J.E.J.R.), University of Sydney, and Cell and Molecular Therapies, Royal Prince Alfred Hospital (J.E.J.R.) — both in Camperdown, NSW, Australia; the Department of Medicine, University of Toronto Faculty of Medicine and St. Michael’s Hospital, Toronto (J.T.); the Department of Pediatrics, Weill Cornell Medical College, New York (C.E.M.); the Department of Medicine, University of Pittsburgh, Pittsburgh (M.V.R.); and Colorado Coagulation, Laboratory Corporation of America Holdings, Englewood, CO (S.T.). Address reprint requests to Dr. George at the Children’s Hospital of Philadelphia, 3401 Civic Center Blvd., Rm. 5016, Philadelphia, PA 19106, or at georgel@email.chop.edu.

 

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