Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) is a rare disease caused by mutations to the UNC13D gene and the subsequent absence or decreased activity of the Munc13-4 protein. Munc13-4 is essential for the exocytosis of perforin and granzyme containing granules from cytotoxic cells. Without it, these cells are able to recognize an immunological insult but are unable to execute their cytotoxic functions. The result is a hyperinflammatory state that, if left untreated, is fatal. At present, the only curative treatment is hematopoietic stem cell transplantation (HSCT), but eligibility and response to this treatment are largely dependent on the ability to control inflammation before HSCT. In this study, we describe an optimized lentiviral vector that can restore Munc13-4 expression and degranulation capacity in both transduced FHL3 patient T cells and transduced hematopoietic stem cells from the FHL3 (Jinx) disease model.

中文翻译：

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由 UNC13D 遗传缺陷引起的 3 型家族性噬血细胞性淋巴组织细胞增生症的慢病毒基因治疗。

家族性噬血细胞性淋巴组织细胞增生症 3 型 (FHL3) 是一种罕见的疾病，由UNC13D突变引起基因以及随后的 Munc13-4 蛋白缺失或活性降低。Munc13-4 对于来自细胞毒性细胞的含穿孔素和颗粒酶的颗粒的胞吐作用是必不可少的。没有它，这些细胞能够识别免疫损伤，但无法执行其细胞毒性功能。结果是过度炎症状态，如果不及时治疗，是致命的。目前，唯一的治愈性治疗是造血干细胞移植 (HSCT)，但这种治疗的资格和反应在很大程度上取决于 HSCT 之前控制炎症的能力。在这项研究中，我们描述了一种优化的慢病毒载体，它可以在转导的 FHL3 患者 T 细胞和来自 FHL3 的转导造血干细胞中恢复 Munc13-4 的表达和脱颗粒能力（Jinx) 疾病模型。