Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators
Abstract Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairm...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-10-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-45376-w |
| _version_ | 1797276553290186752 |
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| author | Anastasia Schultz Shun-Yun Cheng Emily Kirchner Stephanann Costello Heini Miettinen Marta Chaverra Colin King Lynn George Xin Zhao Jana Narasimhan Marla Weetall Susan Slaugenhaupt Elisabetta Morini Claudio Punzo Frances Lefcort |
| author_facet | Anastasia Schultz Shun-Yun Cheng Emily Kirchner Stephanann Costello Heini Miettinen Marta Chaverra Colin King Lynn George Xin Zhao Jana Narasimhan Marla Weetall Susan Slaugenhaupt Elisabetta Morini Claudio Punzo Frances Lefcort |
| author_sort | Anastasia Schultz |
| collection | DOAJ |
| description | Abstract Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients. |
| first_indexed | 2024-03-07T15:29:50Z |
| format | Article |
| id | doaj.art-83a6ea28e4b34dc28cd0386f1edc3e10 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-03-07T15:29:50Z |
| publishDate | 2023-10-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-83a6ea28e4b34dc28cd0386f1edc3e102024-03-05T16:30:46ZengNature PortfolioScientific Reports2045-23222023-10-0113111110.1038/s41598-023-45376-wReduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulatorsAnastasia Schultz0Shun-Yun Cheng1Emily Kirchner2Stephanann Costello3Heini Miettinen4Marta Chaverra5Colin King6Lynn George7Xin Zhao8Jana Narasimhan9Marla Weetall10Susan Slaugenhaupt11Elisabetta Morini12Claudio Punzo13Frances Lefcort14Department of Microbiology and Cell Biology, Montana State UniversityDepartment of Ophthalmology, Neurobiology and Gene Therapy Center, University of Massachusetts Chan Medical SchoolCenter for Genomic Medicine, Massachusetts General Hospital Research InstituteDepartment of Microbiology and Cell Biology, Montana State UniversityDepartment of Microbiology and Cell Biology, Montana State UniversityDepartment of Microbiology and Cell Biology, Montana State UniversityDepartment of Microbiology and Cell Biology, Montana State UniversityDepartment of Microbiology and Cell Biology, Montana State UniversityPTC Therapeutics, Inc.PTC Therapeutics, Inc.PTC Therapeutics, Inc.Center for Genomic Medicine, Massachusetts General Hospital Research InstituteCenter for Genomic Medicine, Massachusetts General Hospital Research InstituteDepartment of Ophthalmology, Neurobiology and Gene Therapy Center, University of Massachusetts Chan Medical SchoolDepartment of Microbiology and Cell Biology, Montana State UniversityAbstract Familial dysautonomia (FD) is a rare neurodevelopmental and neurodegenerative disease caused by a splicing mutation in the Elongator Acetyltransferase Complex Subunit 1 (ELP1) gene. The reduction in ELP1 mRNA and protein leads to the death of retinal ganglion cells (RGCs) and visual impairment in all FD patients. Currently patient symptoms are managed, but there is no treatment for the disease. We sought to test the hypothesis that restoring levels of Elp1 would thwart the death of RGCs in FD. To this end, we tested the effectiveness of two therapeutic strategies for rescuing RGCs. Here we provide proof-of-concept data that gene replacement therapy and small molecule splicing modifiers effectively reduce the death of RGCs in mouse models for FD and provide pre-clinical foundational data for translation to FD patients.https://doi.org/10.1038/s41598-023-45376-w |
| spellingShingle | Anastasia Schultz Shun-Yun Cheng Emily Kirchner Stephanann Costello Heini Miettinen Marta Chaverra Colin King Lynn George Xin Zhao Jana Narasimhan Marla Weetall Susan Slaugenhaupt Elisabetta Morini Claudio Punzo Frances Lefcort Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators Scientific Reports |
| title | Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators |
| title_full | Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators |
| title_fullStr | Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators |
| title_full_unstemmed | Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators |
| title_short | Reduction of retinal ganglion cell death in mouse models of familial dysautonomia using AAV-mediated gene therapy and splicing modulators |
| title_sort | reduction of retinal ganglion cell death in mouse models of familial dysautonomia using aav mediated gene therapy and splicing modulators |
| url | https://doi.org/10.1038/s41598-023-45376-w |
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