美国加州大学洛杉矶分校Donald B. Kohn团队研究了自体慢病毒基因治疗腺苷脱氨酶缺乏症的疗效。2021年5月11日，《新英格兰医学杂志》发表了该研究。

由腺苷脱氨酶（ADA）缺乏症（ADA-SCID）引起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。

研究组用一种实验性基因疗法治疗了50例ADA-SCID患者（其中30例在美国，20例在英国），使用自体CD34+造血干细胞和祖细胞（HSPCs），在体外转导了一种编码人类ADA的自失活慢病毒载体。美国研究随访了24个月，英国研究随访了36个月。

在24个月和36个月的所有研究中，总生存率均为100%。美国研究和英国研究在12个月时的无事件生存率（在没有重新开始酶替代疗法或挽救性异基因造血干细胞移植的情况下）分别为97%和100%；在24个月时分别为97%和95%；在36个月时英国研究为95%。

美国研究30名患者中的29名和英国研究20名患者中的19名持续输注基因修饰的HSPC。患者持续代谢解毒并使ADA活性水平正常化。免疫重建很稳健，美国研究中90%的患者和英国研究中100%的患者分别在24个月和36个月时停止了免疫球蛋白替代治疗。

两项研究中均未发现单克隆扩增、白细胞增生并发症或出现具有复制能力的慢病毒的证据，也没有发生自身免疫或移植物抗宿主病事件。大多数不良事件的等级较低。

研究结果表明，用离体慢病毒HSPC基因疗法治疗ADA-SCID，可显著提高总体和无事件生存率，具有持续的ADA表达、代谢校正和功能性免疫重建。

附：英文原文

Title: Autologous Ex Vivo Lentiviral Gene Therapy for Adenosine Deaminase Deficiency | NEJM

Author: 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.

Issue&Volume: 2021-05-11

Abstract:

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 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.

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 ADA expression, metabolic correction, and functional immune reconstitution.

DOI: 10.1056/NEJMoa2027675

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2027675