Department of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, CA 92697.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
Proc Natl Acad Sci U S A. 2024 Mar 12;121(11):e2316118121. doi: 10.1073/pnas.2316118121. Epub 2024 Mar 5.
Retinitis pigmentosa (RP) is a common form of retinal dystrophy that can be caused by mutations in any one of dozens of rod photoreceptor genes. The genetic heterogeneity of RP represents a significant challenge for the development of effective therapies. Here, we present evidence for a potential gene-independent therapeutic strategy based on targeting , a transcription factor required for the normal differentiation of rod photoreceptors. knockout results in hybrid rod photoreceptors that express the full complement of rod genes, but also a subset of cone genes. We show that germline deletion of potently protects rods in three mechanistically diverse mouse models of retinal degeneration caused by bright-light exposure (light damage), structural deficiency (rhodopsin-deficient mice), or abnormal phototransduction (phosphodiesterase-deficient mice). knockout confers strong neuroprotective effects on rods without adverse effects on their gene expression, structure, or function. Furthermore, in all three degeneration models, prolongation of rod survival by knockout leads to lasting preservation of cone morphology and function. These findings raise the possibility that upregulation of one or more cone genes in -deficient rods may be responsible for the neuroprotective effects we observe.
色素性视网膜炎（RP）是一种常见的视网膜营养不良，可由数十种视杆细胞感光基因中的任何一种突变引起。RP 的遗传异质性对有效治疗方法的开发构成了重大挑战。在这里，我们提出了一种基于靶向的潜在基因独立治疗策略的证据，该策略的靶标是一种转录因子，它是视杆细胞正常分化所必需的。 在缺失导致表达完整的视杆基因，但也表达一部分视锥基因的杂交视杆细胞。我们表明，在由强光照射（光损伤）、结构缺陷（视紫红质缺乏 小鼠）或异常光转导（磷酸二酯酶缺乏 小鼠）引起的三种机制不同的视网膜变性小鼠模型中，生殖系缺失 强烈地保护视杆细胞。 缺失对视杆细胞具有强大的神经保护作用，而对视杆细胞的基因表达、结构或功能没有不良影响。此外，在所有三种变性模型中， 缺失延长视杆细胞的存活时间导致视锥形态和功能的持久保存。这些发现提出了一种可能性，即在 缺乏的视杆细胞中上调一个或多个视锥基因可能是我们观察到的神经保护作用的原因。
