Carriglio Nicola, Klapwijk Jan, Hernandez Raisa Jofra, Vezzoli Michela, Chanut Franck, Lowe Rhiannon, Draghici Elena, Nord Melanie, Albertini Paola, Cristofori Patrizia, Richards Jane, Staton Hazel, Appleby Jonathan, Aiuti Alessandro, Sauer Aisha V
1 Pathogenesis and Therapy of Primary Immunodeficiencies Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET) , IRCCS San Raffaele Scientific Institute, Milan, Italy.
2 GLP SR-TIGET Test Facility , Ospedale San Rafaele, Milan, Italy.
Hum Gene Ther Clin Dev. 2017 Mar;28(1):17-27. doi: 10.1089/humc.2016.191.
GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte antigen-matched related donor is available.
GSK2696273（用编码人腺苷脱氨酶[ADA]酶的逆转录病毒载体转导的自体CD34+细胞）是一种用于治疗腺苷脱氨酶缺乏重症联合免疫缺陷（ADA-SCID）的γ-逆转录病毒离体基因疗法，该疗法针对骨髓来源的CD34+细胞。ADA-SCID是一种严重的单基因疾病，具有免疫和非免疫症状。来自匹配的相关供体的骨髓移植是首选治疗方法，但仅适用于一小部分患者。患者骨髓CD34+细胞的离体基因疗法是一种替代治疗方法。为了准备在欧盟提交上市许可申请，欧洲药品管理局（EMA）要求在小鼠中进行临床前安全性研究。在圣拉斐尔-特雷托基因治疗测试设施按照良好实验室规范（GLP）进行了一项试点研究和一项主要的生物分布研究。在主要研究中，用生产GSK2696273时使用的γ-逆转录病毒载体转导人脐带血（UCB）来源的CD34+细胞。将10只雄性和10只雌性NOD-SCIDγ（NSG）小鼠分为一组，静脉注射单剂量的转导或模拟转导的UCB CD34+细胞，并观察4个月。两组中的大多数动物均观察到血细胞的植入和多系分化。两组之间的嵌合水平无显著差异。在基因治疗组中，在淋巴造血和非淋巴造血组织中均可检测到载体，这与基因修饰的人类造血供体细胞的存在一致。鉴于数据中没有相关的安全问题，GSK2696273的非临床研究和临床经验支持其在欧盟成功申请上市许可，用于治疗没有合适的人类白细胞抗原匹配相关供体的ADA-SCID患者。
