A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases
Abstract Red light optogenetic systems are in high demand for the precise control of gene expression for gene- and cell-based therapies. Here, we report a red/far-red light-inducible photoswitch (REDLIP) system based on the chimeric photosensory protein FnBphP (Fn-REDLIP) or PnBphP (Pn-REDLIP) and t...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54781-2 |
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| author | Longliang Qiao Lingxue Niu Meiyan Wang Zhihao Wang Deqiang Kong Guiling Yu Haifeng Ye |
| author_facet | Longliang Qiao Lingxue Niu Meiyan Wang Zhihao Wang Deqiang Kong Guiling Yu Haifeng Ye |
| author_sort | Longliang Qiao |
| collection | DOAJ |
| description | Abstract Red light optogenetic systems are in high demand for the precise control of gene expression for gene- and cell-based therapies. Here, we report a red/far-red light-inducible photoswitch (REDLIP) system based on the chimeric photosensory protein FnBphP (Fn-REDLIP) or PnBphP (Pn-REDLIP) and their interaction partner LDB3, which enables efficient dynamic regulation of gene expression with a timescale of seconds without exogenous administration of a chromophore in mammals. We use the REDLIP system to establish the REDLIP-mediated CRISPR-dCas9 (REDLIPcas) system, enabling optogenetic activation of endogenous target genes in mammalian cells and mice. The REDLIP system is small enough to support packaging into adeno-associated viruses (AAVs), facilitating its therapeutic application. Demonstrating its capacity to treat metabolic diseases, we show that an AAV-delivered Fn-REDLIP system achieved optogenetic control of insulin expression to effectively lower blood glucose levels in type 1 diabetes model mice and control an anti-obesity therapeutic protein (thymic stromal lymphopoietin, TSLP) to reduce body weight in obesity model mice. REDLIP is a compact and sensitive optogenetic tool for reversible and non-invasive control that can facilitate basic biological and biomedical research. |
| format | Article |
| id | doaj-art-991d0b58d474458d9fc1726267741984 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-991d0b58d474458d9fc17262677419842024-12-01T12:36:01ZengNature PortfolioNature Communications2041-17232024-11-0115111810.1038/s41467-024-54781-2A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseasesLongliang Qiao0Lingxue Niu1Meiyan Wang2Zhihao Wang3Deqiang Kong4Guiling Yu5Haifeng Ye6Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityShanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Center, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal UniversityAbstract Red light optogenetic systems are in high demand for the precise control of gene expression for gene- and cell-based therapies. Here, we report a red/far-red light-inducible photoswitch (REDLIP) system based on the chimeric photosensory protein FnBphP (Fn-REDLIP) or PnBphP (Pn-REDLIP) and their interaction partner LDB3, which enables efficient dynamic regulation of gene expression with a timescale of seconds without exogenous administration of a chromophore in mammals. We use the REDLIP system to establish the REDLIP-mediated CRISPR-dCas9 (REDLIPcas) system, enabling optogenetic activation of endogenous target genes in mammalian cells and mice. The REDLIP system is small enough to support packaging into adeno-associated viruses (AAVs), facilitating its therapeutic application. Demonstrating its capacity to treat metabolic diseases, we show that an AAV-delivered Fn-REDLIP system achieved optogenetic control of insulin expression to effectively lower blood glucose levels in type 1 diabetes model mice and control an anti-obesity therapeutic protein (thymic stromal lymphopoietin, TSLP) to reduce body weight in obesity model mice. REDLIP is a compact and sensitive optogenetic tool for reversible and non-invasive control that can facilitate basic biological and biomedical research.https://doi.org/10.1038/s41467-024-54781-2 |
| spellingShingle | Longliang Qiao Lingxue Niu Meiyan Wang Zhihao Wang Deqiang Kong Guiling Yu Haifeng Ye A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases Nature Communications |
| title | A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases |
| title_full | A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases |
| title_fullStr | A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases |
| title_full_unstemmed | A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases |
| title_short | A sensitive red/far-red photoswitch for controllable gene therapy in mouse models of metabolic diseases |
| title_sort | sensitive red far red photoswitch for controllable gene therapy in mouse models of metabolic diseases |
| url | https://doi.org/10.1038/s41467-024-54781-2 |
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