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通过BCL11A转录后基因沉默策略治疗镰状细胞病
Post-Transcriptional Genetic Silencing of BCL11A to Treat Sickle Cell Disease


Erica B. Esrick ... 其他 • 2021.01.21
相关阅读
• BCL11A基因沉默策略增加镰状细胞病患者的胎儿血红蛋白 • CRISPR-Cas9基因编辑技术治疗镰状细胞病和β地中海贫血 • 输血依赖型β-地中海贫血患者的基因治疗 • 一类通过DNA编辑发挥作用的新型药物

摘要


背景

镰状细胞病的典型表现是溶血性贫血、疼痛和进行性器官损伤。包括α和γ珠蛋白在内的高水平胎儿血红蛋白(HbF)可通过减少镰刀状血红蛋白聚合和红细胞镰状变形来减轻上述表现。BCL11A是对成人红细胞内γ珠蛋白表达和HbF生成具有抑制作用的阻遏蛋白基因。下调该基因是诱导HbF的一种有前景的治疗策略。

 

方法

此项单中心、开放标签的先导性研究纳入了镰状细胞病患者。研究的治疗方法是输入BCH-BB694慢病毒载体转导的自体CD34+细胞,而上述载体编码嵌入微RNA内,靶向BCL11A mRNA的短发夹RNA(shRNA)(shmiR),从而实现红系特异性敲除。本研究评估了患者的主要终点植入情况和安全性,并评估了治疗后的血液学和临床应答情况。

 

结果

截至2020年10月,6例患者已在接受BCH-BB694基因治疗后接受至少6个月随访;中位随访时间为18个月(范围,7~29个月)。所有患者均已实现植入,不良事件与化疗预处理方案的效应一致。可进行全面评估的所有患者均实现了稳健且稳定的HbF诱导(最近一次随访中的HbF/(F+S)百分比,20.4%~41.5%),并且HbF广泛分布在红细胞内(F细胞在并非输入患者体内的红细胞中占58.9%~93.6%),每个F细胞的HbF为9.0~18.6 pg。镰状细胞病的临床表现在随访期间减少或消失。

 

结论

本研究确认,抑制BCL11A是诱导HbF的有效靶点,并提供初步证据表明,基于shmiR的基因敲除策略在镰状细胞病治疗中具有良好的风险-获益特征(由美国国立卫生研究院资助;在ClinicalTrials.gov注册号为NCT03282656)。





作者信息

Erica B. Esrick, M.D., Leslie E. Lehmann, M.D., Alessandra Biffi, M.D., Ph.D., Maureen Achebe, M.D., Christian Brendel, Ph.D., Marioara F. Ciuculescu, M.D., Heather Daley, B.S., Brenda MacKinnon, B.S.N., R.N., Emily Morris, M.P.H., Amy Federico, C.P.N.P., Daniela Abriss, Ph.D., Kari Boardman, B.S., Radia Khelladi, B.S., Kit Shaw, Ph.D., Helene Negre, Ph.D., Olivier Negre, Ph.D., Sarah Nikiforow, M.D., Ph.D., Jerome Ritz, M.D., Sung-Yun Pai, M.D., Wendy B. London, Ph.D., Colleen Dansereau, M.S.N., R.N., C.P.N., Matthew M. Heeney, M.D., Myriam Armant, Ph.D., John P Manis, M.D., and David A. Williams, M.D.
From the Dana–Farber/Boston Children’s Cancer and Blood Disorders Center, Harvard Medical School (E.B.E., L.E.L., A.B., C.B., M.F.C., B.M., K.B., S.-Y.P., W.B.L., C.D., M.M.H., D.A.W.), the Harvard Stem Cell Institute, Harvard Medical School (A.B., C.B.), the Gene Therapy Program, Dana–Farber/Boston Children’s Cancer and Blood Disorders Center (A.B., M.F.C., B.M., E.M., A.F., S.-Y.P., C.D., D.A.W.), the Division of Hematology, Brigham and Women’s Hospital, Harvard Medical School (M. Achebe), the Connell and O’Reilly Families Cell Manipulation Core Facility, Dana–Farber Cancer Institute (H.D., R.K., K.S., H.N., S.N., J.R.), the TransLab, Boston Children’s Hospital (D.A., M. Armant), and the Department of Laboratory Medicine, Boston Children’s Hospital, Harvard Medical School (J.P.M.) — all in Boston; and Bluebird Bio, Cambridge, MA (O.N.). Address reprint requests to Dr. Williams at 300 Longwood Ave., Karp 08125.3, Boston, MA 02115, or at dawilliams@childrens.harvard.edu.

 

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