Chauvin Samuel D, Holley Joe A, Poddar Subhajit, Miner Cathrine A, Kumble Lindsay, Fu Jiayuan, Laue-Gizzi Hanka, Hardy Todd A, Miner Jonathan J
Division of Rheumatology, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
RVCL Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
J Clin Immunol. 2024 Dec 13;45(1):54. doi: 10.1007/s10875-024-01846-y.
TREX1 mutations underlie a variety of human diseases, including retinal vasculopathy with cerebral leukoencephalopathy (RVCL or RVCL-S), a catastrophic adult-onset vasculopathy that is often confused with multiple sclerosis, systemic vasculitis, or systemic lupus erythematosus. Patients with RVCL develop brain, retinal, liver, and kidney disease around age 35-55, leading to premature death in 100% of patients expressing an autosomal dominant C-terminally truncated form of TREX1. We previously demonstrated that RVCL is characterized by high levels of DNA damage, premature cellular senescence, and risk of early-onset breast cancer before age 45. Here, we report human TREX1 mosaicism causing organ-limited RVCL in the retina, as well as a gene therapy to synthetically create TREX1 mosaicism as a potential treatment for RVCL. In our patient with organ-limited disease, the mosaic TREX1 mutant allele underwent germline transmission to 3 children, who developed severe multi-organ disease at ~ age 40, unlike their mosaic parent, who has organ-limited disease at age 74. Additionally, we describe our TREX1 prime editor gene therapy that corrects the most common RVCL-causing TREX1 variant in cell culture and in mice. Thus, TREX1 mosaicism causes organ-limited RVCL with a normal lifespan, suggesting that a gene therapy to create TREX1 mosaicism in adults may someday become useful as a treatment for patients with RVCL.
TREX1基因突变是多种人类疾病的基础，包括伴有脑白质病的视网膜血管病变（RVCL或RVCL-S），这是一种灾难性的成人发病的血管病变，常被误诊为多发性硬化症、系统性血管炎或系统性红斑狼疮。RVCL患者在35至55岁左右会出现脑、视网膜、肝脏和肾脏疾病，100%表达常染色体显性C末端截短形式TREX1的患者会过早死亡。我们之前证明，RVCL的特征是高水平的DNA损伤、过早的细胞衰老以及45岁前患早发性乳腺癌的风险。在这里，我们报告了人类TREX1嵌合现象导致视网膜出现器官局限性RVCL，以及一种通过基因疗法人为制造TREX1嵌合现象作为RVCL潜在治疗方法的研究。在我们患有器官局限性疾病的患者中，嵌合的TREX1突变等位基因通过种系传递给了3个孩子，这些孩子在40岁左右患上了严重的多器官疾病，而他们患有器官局限性疾病的嵌合父母在74岁时仍未发病。此外，我们描述了我们的TREX1碱基编辑器基因疗法，该疗法在细胞培养和小鼠中纠正了最常见的导致RVCL的TREX1变体。因此，TREX1嵌合现象导致器官局限性RVCL但寿命正常，这表明在成年人中制造TREX1嵌合现象的基因疗法有朝一日可能成为治疗RVCL患者的有效方法。
