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腺苷脱氨酶缺乏症的自体离体慢病毒基因疗法
Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency


Donald B. Kohn ... 其他 • 2021.05.27
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• 基因治疗

摘要


背景

腺苷脱氨酶(ADA)缺乏性重度联合免疫缺陷症(ADA-SCID)是罕见且危及生命的原发性免疫缺陷。

 

方法

我们应用试验性基因疗法对50例ADA-SCID患者(美国30例,英国20例)进行了治疗,该疗法含有由编码人ADA的自失活慢病毒载体离体转导的自体CD34+造血干细胞和祖细胞(HSPC)。我们分析了美国两项研究(应用新鲜和冻存制品)的24个月随访数据和英国研究(应用新鲜制品)的36个月随访数据。

 

结果

截至24个月和36个月时,所有研究中的总生存率均为100%。12个月时,无事件生存率(未重新开始接受酶替代疗法或挽救性异基因造血干细胞移植)分别为97%(美国研究)和100%(英国研究);24个月时分别为97%和95%;36个月时为95%(英国研究)。美国研究中30例患者中的29例和英国研究中20例患者中的19例实现遗传修饰HSPC持续植入。患者实现持续性代谢解毒,ADA活性水平恢复正常。免疫重建稳定,截至24个月和36个月时,美国研究中90%的患者和英国研究中100%的患者停止免疫球蛋白替代疗法。无证据表明出现单克隆扩增、白细胞增殖并发症或有复制能力慢病毒,也未发生自身免疫或移植物抗宿主病事件。大多数不良事件的严重程度属于低级别。

 

结论

应用离体慢病毒HSPC基因疗法治疗ADA-SCID可实现较高的总生存率和无事件生存率,并实现ADA持续表达、代谢纠正和功能性免疫重建(由美国国立卫生研究院等资助;在ClinicalTrials.org注册号为NCT01852071、NCT02999984和NCT01380990)。





作者信息

Donald B. Kohn, M.D., Claire Booth, M.B., B.S., Kit L. Shaw, Ph.D., Jinhua Xu-Bayford, D.I.P., Elizabeth Garabedian, R.N., Valentina Trevisan, M.D., Denise A. Carbonaro-Sarracino, Ph.D., Kajal Soni, B.Sc., Dayna Terrazas, R.N., Katie Snell, B.Sc., Alan Ikeda, M.D., Diego Leon-Rico, Ph.D., Theodore B. Moore, M.D., Karen F. Buckland, Ph.D., Ami J. Shah, M.D., Kimberly C. Gilmour, Ph.D., Satiro De Oliveira, M.D., Christine Rivat, Ph.D., Gay M. Crooks, M.B., B.S., Natalia Izotova, B.Sc., John Tse, Pharm.D., Stuart Adams, Ph.D., Sally Shupien, B.A., Hilory Ricketts, B.Sc., Alejandra Davila, B.S., Chilenwa Uzowuru, M.Sc., Amalia Icreverzi, Ph.D., Provaboti Barman, Ph.D., Beatriz Campo Fernandez, Ph.D., Roger P. Hollis, Ph.D., Maritess Coronel, M.S., Allen Yu, B.S., Krista M. Chun, B.S., Christian E. Casas, B.S., Ruixue Zhang, Ph.D., Serena Arduini, Ph.D., Frances Lynn, M.Sc., Mahesh Kudari, M.B., B.S., Andrea Spezzi, M.D., Marco Zahn, M.Sc., Rene Heimke, M.Sc., Ivan Labik, M.Sc., Roberta Parrott, B.S., Rebecca H. Buckley, M.D., Lilith Reeves, M.S., Kenneth Cornetta, M.D., Robert Sokolic, M.D., Michael Hershfield, M.D., Manfred Schmidt, Ph.D., Fabio Candotti, M.D., Harry L. Malech, M.D., Adrian J. Thrasher, M.B., B.S., and H. Bobby Gaspar, M.B., B.S.
From the Departments of Microbiology, Immunology, and Molecular Genetics (D.B.K., K.L.S., D.A.C.-S., D.T., A.D., A. Icreverzi, P.B., B.C.F., R.P.H., M.C., A.Y., K.M.C., C.E.C., R.Z.), Pediatrics (D.B.K., T.B.M., S.D.O., S.S.), and Pathology and Laboratory Medicine (G.M.C.) and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (D.B.K., G.M.C.), University of California, Los Angeles (UCLA), and the Department of Pharmaceutical Services, Ronald Reagan UCLA Medical Center (J.T.), Los Angeles, and Stanford School of Medicine, Palo Alto (A.J.S.) — all in California; University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust (C.B., J.X.-B., V.T., K. Soni, K. Snell, D.L.-R., K.F.B., K.C.G., C.R., N.I., S.A., H.R., C.U., A.J.T., H.B.G.), and Orchard Therapeutics (Europe) (D.A.C.-S., S.A., F.L., M.K., A.S., H.B.G.) — all in London; the National Institute of Allergy and Infectious Diseases (H.L.M.) and the National Human Genome Research Institute (E.G., R.S., F.C.), National Institutes of Health, Bethesda, MD; Cure 4 The Kids Foundation, Las Vegas (A. Ikeda); Cincinnati Children’s Hospital Medical Center, Cincinnati (L.R.); Indiana University School of Medicine, Indianapolis (K.C.); Duke University, Durham, NC (R.P., R.H.B., M.H.); Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (F.C.); and GeneWerk (M.Z., R.H., I.L., M.S.) and the German Cancer Research Center and the National Center for Tumor Diseases (M.Z., M.S.) — all in Heidelberg, Germany. Address reprint requests to Dr. Kohn at the Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, 3163 Terasaki Life Science Bldg., 610 Charles E. Young Dr. South, Los Angeles, CA 90095, or at dkohn1@mednet.ucla.edu.

 

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