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Transl. Med."],"published-print":{"date-parts":[[2026,5,27]]},"abstract":"<jats:p>\n                    Achieving precise temporal control over genome editing is essential for safety but remains a challenge, especially when using small-molecule drugs as external regulators over systems like clustered regularly interspaced short palindromic repeats (CRISPR)\u2013Cas (CRISPR-associated systems). Consequently, controlled therapeutic in situ editing that maintains both precision and efficacy has yet to be demonstrated. Here, we report the PRINCE system, in which nuclease proteins and guide RNAs are both inducible, to deliver programmable nucleases under control more effectively. PRINCE demonstrated temporal precision in human cell cultures over a 2-year period, even after stable genomic integration. The design principles of PRINCE were broadly applicable from CRISPR-Cas9 to a prime editor and also compact programmable nucleases, and the latter platform was named \u201cLittle Prince.\u201d Upon administration of drug inducers, Little Prince, delivered in a single adeno-associated virus vector in situ to humanized mouse models, ameliorated pathological phenotypes of hypercholesterolemia (average reductions of 45 and 47% in serum total cholesterol and low-density lipoprotein cholesterol, respectively) and neovascular age-related macular degeneration, with significantly reduced lesion size and leakage (\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    \u00a0&lt; 0.0001). Last, we demonstrated a consistent and marked reduction in off-target activity across the PRINCE and Little Prince systems in comparison with constitutive editors, with fewer off-target sites and substantially lower editing frequencies, irrespective of nuclease type, delivery method, or genomic target. These results position PRINCE and Little Prince as controlled genome editing platforms with potential for in vivo, particularly in situ, therapeutic applications.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adx7857","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:58:36Z","timestamp":1779904716000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":3,"title":["Coordinated regulation using small-molecule drugs enables controlled therapeutic genome editing and enhanced genomic precision in situ"],"prefix":"10.1126","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-6447-7085","authenticated-orcid":true,"given":"Ju","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China."},{"name":"Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, Shenzhen 518055, China."},{"name":"College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China."},{"name":"Department of Ophthalmology, Eye &amp; ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8978-0864","authenticated-orcid":true,"given":"Li","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8392-369X","authenticated-orcid":true,"given":"Xingyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye &amp; ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China."},{"name":"Shanghai Key Laboratory of Rare Disease Gene Editing and Cell Therapy, Shanghai 200031, China."},{"name":"NHC Key Laboratory of Myopia and Related Eye Diseases Shanghai, Shanghai 200031, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-8270-1928","authenticated-orcid":true,"given":"Yushan","family":"Cai","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China."},{"name":"Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, Shenzhen 518055, China."},{"name":"College of Life Sciences and Oceanography, Shenzhen University, Shenzhen 518060, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shixian","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China."},{"name":"Shenzhen Key Laboratory of Genome Manipulation and Biosynthesis, Shenzhen 518055, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujiao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye &amp; 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