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输血依赖型β-地中海贫血患者的基因治疗
Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia


Alexis A. Thompson ... 其他 • 2018.04.19
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基因治疗地中海贫血初见成效——安全性和有效性得到进一步验证

 

陈彤,高志刚

†复旦大学附属华山医院血液科

‡ National Institute of Alcohol Abuse and Alcoholism, NIH

 

地中海贫血(β-thalassemia)是一种单基因突变引起的遗传性疾病,因患者的血红蛋白β-chain异常,影响红细胞结构和携氧功能而造成贫血等症状。β-珠蛋白完全缺失(β0/β0表形)和严重减少(β0/βE 或β0/β+表形)等重型的地中海贫血患者需要终身定期接受输注红细胞和去铁治疗。异体造血干细胞移植是目前能用的一种可以治愈地中海贫血的方法,其疗效虽然很好,但受限于是否能够找到HLA匹配的骨髓供者或脐血干细胞,以及有移植细胞被排斥的可能和可能发生移植物抗宿主病等情况。

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摘要


背景

移植供者的缺乏和移植相关风险限制了同种异体造血细胞移植在输血依赖型β-地中海贫血患者中的广泛使用。我们此前证明,通过慢病毒转移有标记的β-珠蛋白(βA-T87Q)基因对β-地中海贫血患者进行基因治疗能够替代长期红细胞输入。其后,我们希望评估这种基因治疗在输血依赖型β-地中海贫血患者中的安全性和疗效。

 

方法

在两项1~2期研究中,我们获得了22例输血依赖型β-地中海贫血患者(12~35岁)动员后的自体CD34+细胞,并且使用LentiGlobin BB305载体对这些细胞进行体外转导。该载体编码携带T87Q这一氨基酸取代(HbAT87Q)的成人血红蛋白(HbA)。在这些患者接受白消安清髓性预处理后,将转导后的细胞重新输回患者体内。随后,我们对不良事件、载体整合以及有复制活力的慢病毒水平进行了监测。疗效评估包括总血红蛋白水平、HbAT87Q水平、输血需求和平均载体拷贝数。

 

结果

在输入了经过基因修饰的细胞后中位值26个月(范围,15~42个月),13例具有非β0/β0基因型的患者中,除一例外,全部停止接受红细胞输入;HbAT87Q水平在3.4~10.0 g/dL,总血红蛋白水平在8.2~13.7 g/dL。对血红蛋白水平接近正常范围的患者进行评估显示,红细胞生成异常生物标志物的水平得到了纠正。9例具有β0/β0基因型或双IVS1-110突变拷贝的患者中,年输血量的中位值降低了73%,3例患者停止了红细胞输入。治疗相关不良事件属于自体干细胞移植常见的不良事件。未观察到与载体整合有关的克隆优势。

 

结论

使用BB305载体转导的自体CD34+细胞进行基因治疗,减少或消除了22例重度β-地中海贫血患者的长期红细胞输入需求,且未出现与药物制剂有关的严重不良事件(由蓝鸟生物公司[Bluebird Bio]等资助;HGB-204和HGB-205在ClinicalTrials.gov注册号分别为NCT01745120和NCT02151526)。





作者信息

Alexis A. Thompson, M.D., M.P.H., Mark C. Walters, M.D., Janet Kwiatkowski, M.D., John E.J. Rasko, M.B., B.S., Ph.D., Jean-Antoine Ribeil, M.D., Ph.D., Suradej Hongeng, M.D., Elisa Magrin, Ph.D., Gary J. Schiller, M.D., Emmanuel Payen, Ph.D., Michaela Semeraro, M.D., Ph.D., Despina Moshous, M.D., Ph.D., Francois Lefrere, M.D., Hervé Puy, M.D., Ph.D., Philippe Bourget, Pharm.D., Ph.D., Alessandra Magnani, M.D., Ph.D., Laure Caccavelli, Ph.D., Jean-Sébastien Diana, M.D., Felipe Suarez, M.D., Ph.D., Fabrice Monpoux, M.D., Valentine Brousse, M.D., Catherine Poirot, M.D., Ph.D., Chantal Brouzes, M.D., Jean-François Meritet, Ph.D., Corinne Pondarré, M.D., Ph.D., Yves Beuzard, M.D., Stany Chrétien, Ph.D., Thibaud Lefebvre, M.D., David T. Teachey, M.D., Usanarat Anurathapan, M.D., P. Joy Ho, M.B., B.S., D.Phil., Christof von Kalle, M.D., Ph.D., Morris Kletzel, M.D., Elliott Vichinsky, M.D., Sandeep Soni, M.D., Gabor Veres, Ph.D., Olivier Negre, Ph.D., Robert W. Ross, M.D., David Davidson, M.D., Alexandria Petrusich, B.S., Laura Sandler, M.P.H., Mohammed Asmal, M.D., Ph.D., Olivier Hermine, M.D., Ph.D., Mariane De Montalembert, M.D., Ph.D., Salima Hacein-Bey-Abina, Pharm.D., Ph.D., Stéphane Blanche, M.D., Ph.D., Philippe Leboulch, M.D., and Marina Cavazzana, M.D., Ph.D.
From the Ann and Robert H. Lurie Children’s Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago (A.A.T., M.K.); University of California, San Francisco, Benioff Children’s Hospital, Oakland (M.C.W., E.V.), Lucile Salter Packard Children’s Hospital at Stanford, Palo Alto (S.S.), and David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (G.J.S.) — all in California; Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia (J.K., D.T.T.); Centenary Institute (J.E.J.R.), University of Sydney, Sydney Medical School (J.E.J.R., P.J.H.), and Royal Prince Alfred Hospital (J.E.J.R., P.J.H.), Camperdown, NSW, Australia; Hôpital Universitaire Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris (J.-A.R., E.M., D.M., F.L., P.B., A.M., L.C., J.-S.D., F.S., F.M., V.B., C.B., O.H., M.D.M., S.B., M.C.), Groupe Hospitalier Universitaire Ouest (J.-A.R., A.M., L.C., M.C.), IMAGINE Institute (E.M., M.S., D.M., M.C.), Université Paris Descartes (M.S., C. Poirot, S.H.-B.-A.), Université Paris Diderot (H.P., T.L.), Pierre et Marie Curie University (C. Poirot), and Hôpital Cochin (J.-F.M.), Paris, CEA University Paris-Sud, Institute of Emerging Diseases and Innovative Therapies, Fontenay-aux-Roses (E.P., Y.B., S.C., P.L.), Hôpital Louis-Mourier, Colombes (H.P., T.L.), Centre Hospitalier Intercommunal de Créteil, Créteil (C. Pondarré), and Hôpital Bicêtre, Le Kremlin-Bicêtre (S.H.-B.-A.) — all in France; Bluebird Bio, Cambridge (J.-A.R., S.S., G.V., O.N., R.W.R., D.D., A.P., L.S., M.A.), and Harvard Medical School, Brigham and Women’s Hospital, Boston (P.L.) — both in Massachusetts; Ramathibodi Hospital, Mahidol University, Bangkok, Thailand (S.H., U.A., P.L.); and the National Center for Tumor Diseases–German Cancer Research Center, Heidelberg, Germany (C.K.). Address reprint requests to Dr. Thompson at the Ann and Robert H. Lurie Children’s Hospital of Chicago, Hematology–Oncology, 225 E. Chicago Ave., Box 30, Chicago, IL 60611, or at a-thompson@northwestern.edu; to Dr. Walters at mwalters@mail.cho.org; to Dr. Leboulch at pleboulch@rics.bwh.harvard.edu; or to Dr. Cavazzana at m.cavazzana@aphp.fr.

 

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