近日，英国伦敦大学学院Claire Booth团队研究了基因治疗腺苷脱氨酶缺乏症的长期安全性和有效性。这一研究成果发表在2025年10月16日出版的《新英格兰医学杂志》上。

由腺苷脱氨酶（ADA）缺乏引起的严重联合免疫缺陷（SCID）是一种危及生命的先天性免疫缺陷，慢病毒基因治疗已在临床试验中进行了研究。

在2012年至2019年期间，研究组对患有ADA-SCID的患者进行了白消安非清髓调节治疗，然后用慢病毒载体编码的人ADA体外转导的自体CD34+造血干细胞移植。主要疗效终点是总生存期和无事件生存期（定义为无抢救异基因造血干细胞移植、重新启动酶替代治疗和额外基因治疗的生存期）。次要终点包括未接受免疫球蛋白替代治疗，存在破伤风或肺炎球菌疫苗的保护性滴度，以及持续停止真菌或病毒预防。研究组现在报告了该队列的长期预后，代表474患者年的随访，中位随访时间为7.5年。

研究组在美国（33名患者）和英国（29名患者）治疗了62名ADA-SCID患者。总生存率为100%，无事件生存率为95%（62名患者中有59名）。在6个月时成功植入基因标记的59名患者在最后一次随访中继续没有接受酶替代治疗，并且基因标记、ADA酶活性、代谢排毒和免疫重建稳定；其中58名患者（98%）停止了IgG替代治疗，并有证据表明对疫苗接种有强烈反应。所有患者均未出现白细胞增殖事件或克隆性扩增。

在大型患者队列中的这些长期发现表明，自体CD34+造血干细胞慢病毒基因治疗ADA-SCID具有持续的临床疗效和安全性，表明这是一种治愈性治疗方法。

附：英文原文

Title: Long-Term Safety and Efficacy of Gene Therapy for Adenosine Deaminase Deficiency

Author: Claire Booth, Katelyn Masiuk, Konstantinos Vazouras, Augustine Fernandes, Jinhua Xu-Bayford, Beatriz Campo Fernandez, Sohini Roy, Beatrice Curio-Penny, Jordyn Arnold, Dayna Terrazas, Jack Reid, Kimberly C. Gilmour, Stuart Adams, Elena Alvarez Mediavilla, Lana Mhaldien, Grainne O’Toole, Rima Ahmed, Elizabeth Garabedian, Harry Malech, Suk See De Ravin, Theodore B. Moore, Satiro De Oliveira, Danilo Pellin, Tsai-Yu Lin, Thao Thi Dang, Kenneth Cornetta, Michael S. Hershfield, Havinder Hara, Adrian J. Thrasher, H. Bobby Gaspar, Donald B. Kohn

Issue&Volume: 2025-10-16

Abstract:

BACKGROUND

Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a life-threatening inborn error of immunity for which lentiviral gene therapy has been investigated in clinical trials.

METHODS

Between 2012 and 2019, we treated patients who had ADA-SCID with busulfan nonmyeloablative conditioning followed by transplantation with autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding human ADA. The primary efficacy end points were overall survival and event-free survival (defined as survival free from rescue allogeneic hematopoietic stem-cell transplantation, reinitiation of enzyme-replacement therapy, and additional gene therapy). Secondary end points included no receipt of immunoglobulin-replacement therapy, the presence of protective titers to tetanus or pneumococcal vaccines, and sustained discontinuation of fungal or viral prophylaxis. We now report the long-term results from this cohort representing 474 patient-years of follow-up, with a median follow-up of 7.5 years.

RESULTS

We treated 62 patients with ADA-SCID in the United States (33 patients) and the United Kingdom (29 patients). Overall survival was 100%, and event-free survival was 95% (59 of 62 patients). All 59 patients who had successful gene-marked engraftment at 6 months have continued not to receive enzyme-replacement therapy and have had stable gene marking, ADA enzyme activity, metabolic detoxification, and immune reconstitution through the last follow-up; 58 of these patients (98%) discontinued IgG replacement therapy and have evidence of a robust response to vaccinations. None of the patients had a leukoproliferative event or clonal expansion.

CONCLUSIONS

These long-term findings in a large patient cohort show the sustained clinical efficacy and safety of autologous CD34+ hematopoietic stem-cell lentiviral gene therapy for ADA-SCID, indicating that it is a curative treatment.

DOI: NJ202510163931509

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2502754