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Patients with RVCL develop brain, retinal, liver, and kidney disease around age 35\u201355, 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\n                    <jats:italic>TREX1<\/jats:italic>\n                    mosaicism causing organ-limited RVCL in the retina, as well as a gene therapy to synthetically create\n                    <jats:italic>TREX1<\/jats:italic>\n                    mosaicism as a potential treatment for RVCL. In our patient with organ-limited disease, the mosaic\n                    <jats:italic>TREX1<\/jats:italic>\n                    mutant allele underwent germline transmission to 3 children, who developed severe multi-organ disease at ~\u2009age 40, unlike their mosaic parent, who has organ-limited disease at age 74. Additionally, we describe our\n                    <jats:italic>TREX1<\/jats:italic>\n                    prime editor gene therapy that corrects the most common RVCL-causing\n                    <jats:italic>TREX1<\/jats:italic>\n                    variant in cell culture and in mice. Thus,\n                    <jats:italic>TREX1<\/jats:italic>\n                    mosaicism causes organ-limited RVCL with a normal lifespan, suggesting that a gene therapy to create\n                    <jats:italic>TREX1<\/jats:italic>\n                    mosaicism in adults may someday become useful as a treatment for patients with RVCL.\n                  <\/jats:p>","DOI":"10.1007\/s10875-024-01846-y","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T03:31:21Z","timestamp":1734060681000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Prime Editor Gene Therapy and TREX1 Mosaicism in Retinal Vasculopathy with Cerebral Leukoencephalopathy"],"prefix":"10.1007","volume":"45","author":[{"given":"Samuel D.","family":"Chauvin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe A.","family":"Holley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Subhajit","family":"Poddar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathrine A.","family":"Miner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsay","family":"Kumble","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanka","family":"Laue-Gizzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd A.","family":"Hardy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Miner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,13]]},"reference":[{"issue":"3","key":"1846_CR1","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1007\/s10875-015-0147-3","volume":"35","author":"GI Rice","year":"2015","unstructured":"Rice GI, Rodero MP, Crow YJ. Human Disease Phenotypes Associated with mutations in TREX1. J Clin Immunol. 2015;35(3):235\u201343.","journal-title":"J Clin Immunol"},{"issue":"4","key":"1846_CR2","doi-asserted-by":"publisher","first-page":"811","DOI":"10.1086\/513443","volume":"80","author":"G Rice","year":"2007","unstructured":"Rice G, Newman WG, Dean J, Patrick T, Parmar R, Flintoff K, et al. Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome. Am J Hum Genet. 2007;80(4):811\u20135.","journal-title":"Am J Hum Genet"},{"issue":"9","key":"1846_CR3","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1038\/ng2082","volume":"39","author":"A Richards","year":"2007","unstructured":"Richards A, van den Maagdenberg AMJM, Jen JC, Kavanagh D, Bertram P, Spitzer D, et al. C-terminal truncations in human 3\u2032-5\u2032 DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. 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