In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration
Abstract Retinal degenerative diseases, such as retinitis pigmentosa (RP) and age‑related macular degeneration (AMD), lead to progressive vision loss through photoreceptor degeneration; RP begins with the gradual loss of peripheral rods, whereas AMD causes central‑vision loss mainly because macular...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-07299-6 |
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| author | Hyungwoo Lee Hyoik Jang Jae-Byoung Chae Hyo Kyung Lee Chanok Son Chul-Woo Park Taejeong Ha Munjeong Yum Sungmi Park Sun Woo Hong Suk Young Lee Jungmook Lyu Semin Lee Dong Ki Lee Hyewon Chung |
| author_facet | Hyungwoo Lee Hyoik Jang Jae-Byoung Chae Hyo Kyung Lee Chanok Son Chul-Woo Park Taejeong Ha Munjeong Yum Sungmi Park Sun Woo Hong Suk Young Lee Jungmook Lyu Semin Lee Dong Ki Lee Hyewon Chung |
| author_sort | Hyungwoo Lee |
| collection | DOAJ |
| description | Abstract Retinal degenerative diseases, such as retinitis pigmentosa (RP) and age‑related macular degeneration (AMD), lead to progressive vision loss through photoreceptor degeneration; RP begins with the gradual loss of peripheral rods, whereas AMD causes central‑vision loss mainly because macular cones and parafoveal rods degenerate. The neural retina leucine zipper (NRL) directs rod photoreceptor differentiation, and its disruption has been linked to upregulated cone-specific markers in rods. This study investigates the therapeutic potential of a cell-penetrating asymmetric small interfering RNA targeting NRL (cp-asiNRL) to induce rod-to-cone conversion and mitigate retinal degeneration. cp-asiNRL was administered intravitreally to C57BL/6J wild-type (WT), neovascular AMD (nAMD), and RP (RhoP23H/+) mouse models. Subsequent analyses included cone marker expression levels and electroretinographic evaluations, and single-cell RNA sequencing. Administration of cp-asiNRL suppressed NRL expression, increased cone marker expression, and improved retinal function in both WT and nAMD models. In RP mice, cone marker expression was also elevated, although functional improvements were comparatively modest, likely reflecting the advanced disease stage. Single-cell RNA sequencing revealed a rod-to-cone-like transdifferentiation, suggesting that cp-asiNRL-mediated NRL knockdown partially preserved photoreceptor integrity. cp-asiNRL-mediated NRL silencing shows considerable promise as a therapeutic intervention for retinal degenerative conditions. By promoting rod-to-cone transdifferentiation and supporting photoreceptor survival, this approach may offer a novel strategy for vision preservation. |
| format | Article |
| id | doaj-art-a01244bb696e4ffdb91fef452bfc9eb0 |
| institution | DOAJ |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-a01244bb696e4ffdb91fef452bfc9eb02025-08-20T03:05:18ZengNature PortfolioScientific Reports2045-23222025-07-0115111410.1038/s41598-025-07299-6In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degenerationHyungwoo Lee0Hyoik Jang1Jae-Byoung Chae2Hyo Kyung Lee3Chanok Son4Chul-Woo Park5Taejeong Ha6Munjeong Yum7Sungmi Park8Sun Woo Hong9Suk Young Lee10Jungmook Lyu11Semin Lee12Dong Ki Lee13Hyewon Chung14Department of Ophthalmology, Konkuk University College of MedicineOliX Pharmaceuticals, Inc.Department of Ophthalmology, Konkuk University College of MedicineDepartment of Biomedical Engineering, Ulsan National Institute of Science and TechnologyDepartment of Ophthalmology, Konkuk University College of MedicineDepartment of Ophthalmology, Konkuk University College of MedicineOliX Pharmaceuticals, Inc.OliX Pharmaceuticals, Inc.OliX Pharmaceuticals, Inc.OliX Pharmaceuticals, Inc.Department of Chemistry, Sungkyunkwan UniversityDepartment of Medical Science, Myung-Gok Eye Research Institute, Konyang UniversityDepartment of Biomedical Engineering, Ulsan National Institute of Science and TechnologyOliX Pharmaceuticals, Inc.Department of Ophthalmology, Konkuk University College of MedicineAbstract Retinal degenerative diseases, such as retinitis pigmentosa (RP) and age‑related macular degeneration (AMD), lead to progressive vision loss through photoreceptor degeneration; RP begins with the gradual loss of peripheral rods, whereas AMD causes central‑vision loss mainly because macular cones and parafoveal rods degenerate. The neural retina leucine zipper (NRL) directs rod photoreceptor differentiation, and its disruption has been linked to upregulated cone-specific markers in rods. This study investigates the therapeutic potential of a cell-penetrating asymmetric small interfering RNA targeting NRL (cp-asiNRL) to induce rod-to-cone conversion and mitigate retinal degeneration. cp-asiNRL was administered intravitreally to C57BL/6J wild-type (WT), neovascular AMD (nAMD), and RP (RhoP23H/+) mouse models. Subsequent analyses included cone marker expression levels and electroretinographic evaluations, and single-cell RNA sequencing. Administration of cp-asiNRL suppressed NRL expression, increased cone marker expression, and improved retinal function in both WT and nAMD models. In RP mice, cone marker expression was also elevated, although functional improvements were comparatively modest, likely reflecting the advanced disease stage. Single-cell RNA sequencing revealed a rod-to-cone-like transdifferentiation, suggesting that cp-asiNRL-mediated NRL knockdown partially preserved photoreceptor integrity. cp-asiNRL-mediated NRL silencing shows considerable promise as a therapeutic intervention for retinal degenerative conditions. By promoting rod-to-cone transdifferentiation and supporting photoreceptor survival, this approach may offer a novel strategy for vision preservation.https://doi.org/10.1038/s41598-025-07299-6 |
| spellingShingle | Hyungwoo Lee Hyoik Jang Jae-Byoung Chae Hyo Kyung Lee Chanok Son Chul-Woo Park Taejeong Ha Munjeong Yum Sungmi Park Sun Woo Hong Suk Young Lee Jungmook Lyu Semin Lee Dong Ki Lee Hyewon Chung In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration Scientific Reports |
| title | In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration |
| title_full | In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration |
| title_fullStr | In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration |
| title_full_unstemmed | In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration |
| title_short | In vivo efficacy of NRL knockdown with cell-penetrating siRNA in retinal degeneration |
| title_sort | in vivo efficacy of nrl knockdown with cell penetrating sirna in retinal degeneration |
| url | https://doi.org/10.1038/s41598-025-07299-6 |
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