Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL is caused by inactivating mutations in proteins that regulate cellular immunity. Here, we used an adeno-associated virus–based CRISPR-Cas9 system with an inhibitor of nonhomologous end joining to repair such mutations in potentially long-lived T cells ex vivo. Repaired CD8 memory T cells efficiently cured lethal hyperinflammation in a mouse model of Epstein-Barr virus–triggered FHL2, a subtype caused by perforin-1 ( Prf1 ) deficiency. Furthermore, repair of PRF1 and Munc13-4 ( UNC13D )—whose deficiency causes the FHL subtype FHL3—in mutant memory T cells from two critically ill patients with FHL restored T cell cytotoxicity. These results provide a starting point for the treatment of genetic T cell immune dysregulation syndromes with repaired autologous T cells.

中文翻译：

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自体记忆 T 细胞中的精确 CRISPR-Cas9 基因修复治疗家族性噬血细胞性淋巴组织细胞增多症

家族性噬血细胞性淋巴组织细胞增多症 (FHL) 是一种遗传性的、通常致命的免疫缺陷，其特征是严重的全身过度炎症。尽管同种异体骨髓移植可以治愈，但迫切需要更有效的治疗方法。 FHL 是由调节细胞免疫的蛋白质失活突变引起的。在这里，我们使用基于腺相关病毒的 CRISPR-Cas9 系统和非同源末端连接抑制剂来离体修复潜在长寿 T 细胞中的此类突变。修复的 CD8 记忆 T 细胞有效治愈了由 Epstein-Barr 病毒触发的 FHL2（一种由穿孔素-1 引起的亚型）小鼠模型中的致命性过度炎症。普罗夫1) 不足。此外，修复脉冲频率1和 Munc13-4 (UNC13D）——其缺陷导致 FHL 亚型 FHL3——来自两名 FHL 危重患者的突变记忆 T 细胞恢复了 T 细胞的细胞毒性。这些结果为利用修复的自体 T 细胞治疗遗传性 T 细胞免疫失调综合征提供了一个起点。