Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.
Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency.
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DOI：
10.1056/nejmoa2027675
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发表时间：
2021-05-27
期刊：
影响因子：
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通讯作者：
Gaspar HB
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作者：
Kohn DB;Booth C;Shaw KL;Xu-Bayford J;Garabedian E;Trevisan V;Carbonaro-Sarracino DA;Soni K;Terrazas D;Snell K;Ikeda A;Leon-Rico D;Moore TB;Buckland KF;Shah AJ;Gilmour KC;De Oliveira S;Rivat C;Crooks GM;Izotova N;Tse J;Adams S;Shupien S;Ricketts H;Davila A;Uzowuru C;Icreverzi A;Barman P;Campo Fernandez B;Hollis RP;Coronel M;Yu A;Chun KM;Casas CE;Zhang R;Arduini S;Lynn F;Kudari M;Spezzi A;Zahn M;Heimke R;Labik I;Parrott R;Buckley RH;Reeves L;Cornetta K;Sokolic R;Hershfield M;Schmidt M;Candotti F;Malech HL;Thrasher AJ;Gaspar HB
腺苷脱氨酶（ADA）缺乏引起的严重联合免疫缺陷（ADA-SCID）是一种罕见的、危及生命的原发性免疫缺陷。我们用研究性基因疗法治疗了50例ADA-SCID患者（30例在美国，20例在英国），该基因疗法由用编码人ADA的自失活慢病毒载体离体转导的自体CD 34+造血干细胞和祖细胞（HSPC）组成。分析了两项美国研究（使用新鲜和冷冻保存制剂）24个月随访时的数据以及英国的数据。研究（其中使用新鲜制剂）在36个月随访时。在所有研究中，24和36个月的总生存率为100%。无事件生存率（在没有重新开始酶替代疗法或补救性异基因造血干细胞移植的情况下）为97%（美国研究）和100%（英国研究）。研究）; 24个月时分别为97%和95%; 95%（英国）研究）36个月。在美国研究中，30例患者中有29例持续植入转基因HSPC，在英国研究中，20例患者中有19例持续植入转基因HSPC。study.患者持续代谢解毒和ADA活性水平正常化。免疫重建是稳健的，美国研究中90%的患者和英国100%的患者。研究分别在24个月和36个月时停止免疫球蛋白替代疗法。未观察到单克隆扩增、白细胞增殖性并发症或复制型慢病毒出现的证据，也未发生自身免疫或移植物抗宿主病事件。大多数不良事件为低级别。用离体慢病毒HSPC基因疗法治疗ADA-SCID导致较高的总体和无事件生存期，并伴有持续的ADA表达、代谢校正和功能性免疫重建。（由美国国立卫生研究院和其他机构资助; ClinicalTrials.gov编号，NCT 01852071，NCT 02999984和NCT 01380990。
Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. 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 ADA. 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. 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. Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. (Funded by the National Institutes of Health and others; ClinicalTrials.gov numbers, NCT01852071, NCT02999984, and NCT01380990.)