Prime Editor Gene Therapy and TREX1 Mosaicism in Retinal Vasculopathy with Cerebral Leukoencephalopathy

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.