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Mol. Life Sci."],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a <jats:italic>Pde6b<\/jats:italic>-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16\u00a0weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24\u00a0weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24\u00a0weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization.<\/jats:p>","DOI":"10.1007\/s00018-022-04161-0","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T14:05:23Z","timestamp":1645625123000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model"],"prefix":"10.1007","volume":"79","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-6539","authenticated-orcid":false,"given":"Jacqueline","family":"Kajtna","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9082-2427","authenticated-orcid":false,"given":"Stephen H.","family":"Tsang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9966-113X","authenticated-orcid":false,"given":"Susanne F.","family":"Koch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,2,23]]},"reference":[{"issue":"8","key":"4161_CR1","doi-asserted-by":"publisher","first-page":"5836","DOI":"10.1167\/iovs.13-12557","volume":"54","author":"K Ratnam","year":"2013","unstructured":"Ratnam K, Carroll J, Porco TC et al (2013) Relationship between foveal cone structure and clinical measures of visual function in patients with inherited retinal degenerations. 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