腺苷脱氨酶缺乏症的自体体外慢病毒基因治疗。
Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.
机构信息
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.
出版信息
N Engl J Med. 2021 May 27;384(21):2002-2013. doi: 10.1056/NEJMoa2027675. Epub 2021 May 11.
BACKGROUND
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency.
METHODS
We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human . Data from the two U.S. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. study (in which a fresh formulation was used) at 36 months of follow-up.
RESULTS
Overall survival was 100% in all studies up to 24 and 36 months. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. studies) and 100% (U.K. study) at 12 months; 97% and 95%, respectively, at 24 months; and 95% (U.K. study) at 36 months. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. studies and in 19 of 20 patients in the U.K. study. Patients had sustained metabolic detoxification and normalization of ADA activity levels. Immune reconstitution was robust, with 90% of the patients in the U.S. studies and 100% of those in the U.K. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. Most adverse events were of low grade.
CONCLUSIONS
Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.).
背景
由于腺苷脱氨酶（ADA）缺乏（ADA-SCID）导致的严重联合免疫缺陷是一种罕见且危及生命的原发性免疫缺陷。
方法
我们用一种研究性基因疗法治疗了 50 例 ADA-SCID 患者（美国 30 例，英国 20 例），该疗法由自体 CD34+造血干细胞和祖细胞（HSPC）组成，这些细胞经自体失活慢病毒载体体外转导，该载体编码人类 ADA。对美国两项研究（分别使用新鲜制剂和冷冻保存制剂）的 24 个月随访数据和英国一项研究（使用新鲜制剂）的 36 个月随访数据进行了分析。
结果
所有研究在 24 个月和 36 个月时的总生存率均为 100%。无事件生存（无酶替代疗法再启动或挽救性同种异体造血干细胞移植）率在 12 个月时为 97%（美国研究）和 100%（英国研究）；在 24 个月时分别为 97%和 95%；在 36 个月时分别为 95%（英国研究）。在 30 例美国研究患者和 20 例英国研究患者中，有 29 例和 19 例患者的基因修饰 HSPC 持续植入。患者持续进行代谢解毒，ADA 活性水平正常化。免疫重建非常强大，美国研究的 90%和英国研究的 100%患者分别在 24 个月和 36 个月时停止免疫球蛋白替代治疗。未发现单克隆扩增、白细胞增生性并发症或复制性慢病毒的出现，也未发生自身免疫或移植物抗宿主病。大多数不良事件为低级别。
结论
用体外慢病毒 HSPC 基因疗法治疗 ADA-SCID 可实现高总生存率和无事件生存率，并持续表达、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；ClinicalTrials.gov 编号：NCT01852071、NCT02999984 和 NCT01380990）。
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