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Among these, mutations in PDE6A, responsible for encoding a cGMP\u2010specific phosphodiesterase, stand out as pivotal in autosomal recessive RP (RP43). Unfortunately, no effective therapy currently exists for this specific form of RP. However, recent advancements in genome editing, such as base editing (BE) and prime editing (PE), offer a promising avenue for precise and efficient gene therapy. Here, it is illustrated that the engineered BE and PE systems, particularly PE, exhibit high efficiency in rescuing a target point mutation with minimal bystander effects in an RP mouse model carrying the <jats:italic>Pde6a<\/jats:italic> (c.2009A &gt; G, p.D670G) mutation. The optimized BE and PE systems are first screened in N2a cells and subsequently assessed in electroporated mouse retinas. Notably, the optimal PE system, delivered via dual adeno\u2010associated virus (AAV), precisely corrects the pathogenic mutation with average 9.4% efficiency, with no detectable bystander editing. This correction restores PDE6A protein expression, preserved photoreceptors, and rescued retinal function in <jats:italic>Pde6a<\/jats:italic> mice. Therefore, this study offers a proof\u2010of\u2010concept demonstration for the treatment of <jats:italic>Pde6a<\/jats:italic>\u2010related retinal degeneration using BE and PE systems.<\/jats:p>","DOI":"10.1002\/advs.202405628","type":"journal-article","created":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T06:46:28Z","timestamp":1726728388000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Efficient Rescue of Retinal Degeneration in <i>Pde6a<\/i> Mice by Engineered Base Editing and Prime Editing"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5433-5656","authenticated-orcid":false,"given":"Zhiquan","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander E.","family":"Davis","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien\u2010Hui","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingting","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"},{"name":"Department of Ophthalmology Shanghai East Hospital Tongji University School of Medicine  Shanghai 200120 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Ning","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sui","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8735-4765","authenticated-orcid":false,"given":"Yang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Stanford University School of Medicine  Palo Alto CA 94304 USA"},{"name":"Palo Alto Veterans Administration  Palo Alto CA 94304 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,9,19]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-95046-4_25"},{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/0039-6257(88)90085-9"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-030-27378-1_17"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2020.4206"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.63.5.9"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn327"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.156"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds466"},{"key":"e_1_2_9_5_3","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt452"},{"key":"e_1_2_9_6_1","first-page":"782","volume":"64","author":"Reichel F. 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