本文由小咖机器人翻译整理

期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-023-02789-4

摘要内容如下：

腺苷脱氨酶（ADA）缺乏导致严重联合免疫缺陷（SCID）。先前的临床试验表明，白消安降低强度预处理后的自体CD34+细胞基因治疗（GT）是ADA-SCID的一种很有前途的治疗方法，但长期数据是有保证的。在此，我们报告了对43例接受逆转录病毒体外骨髓来源的造血干细胞GT治疗的ADA-SCID患者的长期安全性和有效性数据的分析。22名患者（中位随访时间15.4年）在临床开发或指定患者计划中接受治疗。19名患者在上市授权后接受了治疗（中位随访时间为3.2年），另外2名患者接受了动员的外周血CD34+细胞GT。数据截止时，所有43例患者均存活，中位随访时间为5.0年（四分位间距2.4-15.4），2年无干预生存率（无需长期酶替代治疗或异基因造血干细胞移植）为88%（95%置信区间78.7-98.4%）。大多数不良事件/反应与疾病背景、白消安预处理或免疫重建有关；真实世界经验的安全性与上市前队列一致。命名患者计划中的一名患者在GT后4.7年发生了与治疗相关的T细胞白血病，目前处于缓解期。观察到多谱系基因校正细胞的长期存在、代谢解毒、免疫重建和感染率降低。估计的混合效应模型显示，较高剂量的CD34+细胞输注和较年轻的GT年龄对CD3+转导细胞、淋巴细胞和CD4+CD45RA+初始T细胞的平台期有积极影响，而细胞剂量对CD15+转导细胞的最终平台期有积极影响。这些长期数据表明，GT在ADA中的风险效益仍然是有利的，并保证继续进行长期安全性监测。临床试验注册：NCT00598481，NCT03478670。

英文原文如下：

Abstracts

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .

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