1 San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute , Milan, Italy.
2 Vita-Salute San Raffaele University , Milan, Italy .
Hum Gene Ther. 2017 Nov;28(11):972-981. doi: 10.1089/hum.2017.175.
Twenty-five years have passed since first attempts of gene therapy (GT) in children affected by severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) defect, also known by the general public as bubble babies. ADA-SCID is fatal early in life if untreated. Unconditioned hematopoietic stem cell (HSC) transplant from matched sibling donor represents a curative treatment but is available for few patients. Enzyme replacement therapy can be life-saving, but its chronic use has many drawbacks. This review summarizes the history of ADA-SCID GT over the last 25 years, starting from first pioneering studies in the early 1990s using gamma-retroviral vectors, based on multiple infusions of genetically corrected autologous peripheral blood lymphocytes. HSC represented the ideal target for gene correction to guarantee production of engineered multi-lineage progeny, but it required a decade to achieve therapeutic benefit with this approach. Introduction of low-intensity conditioning represented a crucial step in achieving stable gene-corrected HSC engraftment and therapeutic levels of ADA-expressing cells. Recent clinical trials demonstrated that gamma-retroviral GT for ADA-SCID has a favorable safety profile and is effective in restoring normal purine metabolism and immune functions in patients >13 years after treatment. No abnormal clonal proliferation or leukemia development have been observed in >40 patients treated experimentally in five different centers worldwide. In 2016, the medicinal product Strimvelis™ received marketing approval in Europe for patients affected by ADA-SCID without a suitable human leukocyte antigen-matched related donor. Positive safety and efficacy results have been obtained in GT clinical trials using lentiviral vectors encoding ADA. The results obtained in last 25 years in ADA-SCID GT development fundamentally contributed to improve patients' prognosis, together with earlier diagnosis thanks to newborn screening. These advances open the way to further clinical development of GT as treatment for broader applications, from inherited diseases to cancer.
25 年前，首例严重联合免疫缺陷症（SCID）患儿的基因治疗（GT）尝试获得成功，这些患儿因腺苷脱氨酶（ADA）缺陷而患病，公众通常称之为“泡泡婴儿”。如果不进行治疗，ADA-SCID 患儿会在生命早期夭折。未预处理的情况下，来自匹配的同胞供体的未条件化造血干细胞（HSC）移植是一种根治性治疗方法，但只有少数患者适用。酶替代疗法可以救命，但长期使用存在许多缺点。本文综述了过去 25 年来 ADA-SCID GT 的历史，从 20 世纪 90 年代早期使用基于多次输注基因修正自体外周血淋巴细胞的γ-逆转录病毒载体的开创性研究开始。HSC 是基因修正的理想靶标，可保证产生工程多谱系后代，但该方法需要十年才能获得治疗益处。低强度预处理的引入是实现稳定的基因修正 HSC 植入和治疗水平 ADA 表达细胞的关键步骤。最近的临床试验表明，ADA-SCID 的γ-逆转录病毒 GT 具有良好的安全性，可有效恢复患者的嘌呤代谢和免疫功能。在全球五个不同中心进行的 50 多例实验性治疗患者中，未观察到异常克隆性增殖或白血病发展。2016 年，Strimvelis™在欧洲获得批准上市，用于无合适人类白细胞抗原匹配相关供体的 ADA-SCID 患者。使用编码 ADA 的慢病毒载体进行 GT 临床试验获得了积极的安全性和疗效结果。过去 25 年在 ADA-SCID GT 发展方面取得的成果，与由于新生儿筛查而更早的诊断一起，从根本上改善了患者的预后。这些进展为 GT 作为更广泛应用（从遗传性疾病到癌症）的治疗方法的进一步临床开发铺平了道路。
