In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina
Efficacy and safety considerations constitute essential steps during development of in vivo gene therapies. Herein, we evaluated efficacy and safety of splice factor-based treatments to correct mutation-induced splice defects in an <i>Opa1</i> mutant mouse line. We applied adeno-associat...
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MDPI AG
2023-03-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/6/955 |
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| author | Sebastian Swirski Oliver May Malte Ahlers Bernd Wissinger Martin Greschner Christoph Jüschke John Neidhardt |
| author_facet | Sebastian Swirski Oliver May Malte Ahlers Bernd Wissinger Martin Greschner Christoph Jüschke John Neidhardt |
| author_sort | Sebastian Swirski |
| collection | DOAJ |
| description | Efficacy and safety considerations constitute essential steps during development of in vivo gene therapies. Herein, we evaluated efficacy and safety of splice factor-based treatments to correct mutation-induced splice defects in an <i>Opa1</i> mutant mouse line. We applied adeno-associated viruses to the retina. The viruses transduced retinal cells with an engineered U1 snRNA splice factor designed to correct the <i>Opa1</i> splice defect. We found the treatment to be efficient in increasing wild-type <i>Opa1</i> transcripts. Correspondingly, Opa1 protein levels increased significantly in treated eyes. Measurements of retinal morphology and function did not reveal therapy-related side-effects supporting the short-term safety of the treatment. Alterations of potential off-target genes were not detected. Our data suggest that treatments of splice defects applying engineered U1 snRNAs represent a promising in vivo therapeutic approach. The therapy increased wild-type <i>Opa1</i> transcripts and protein levels without detectable morphological, functional or genetic side-effects in the mouse eye. The U1 snRNA-based therapy can be tailored to specific disease gene mutations, hence, raising the possibility of a wider applicability of this promising technology towards treatment of different inherited retinal diseases. |
| first_indexed | 2024-03-11T06:47:28Z |
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| id | doaj.art-38d7d37af2a440cab3ab5e7ec94621ad |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T06:47:28Z |
| publishDate | 2023-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-38d7d37af2a440cab3ab5e7ec94621ad2023-11-17T10:14:13ZengMDPI AGCells2073-44092023-03-0112695510.3390/cells12060955In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse RetinaSebastian Swirski0Oliver May1Malte Ahlers2Bernd Wissinger3Martin Greschner4Christoph Jüschke5John Neidhardt6Human Genetics, Department of Human Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, GermanyHuman Genetics, Department of Human Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, GermanyVisual Neuroscience, Department of Neuroscience, Faculty of Medicine and Health Sciences, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, GermanyInstitute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Elfriede-Aulhorn-Straße 7, 72076 Tübingen, GermanyInstitute for Ophthalmic Research, Centre for Ophthalmology, University of Tübingen, Elfriede-Aulhorn-Straße 7, 72076 Tübingen, GermanyHuman Genetics, Department of Human Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, GermanyHuman Genetics, Department of Human Medicine, Faculty of Medicine and Health Sciences, University of Oldenburg, Carl-von-Ossietzky-Straße 9-11, 26129 Oldenburg, GermanyEfficacy and safety considerations constitute essential steps during development of in vivo gene therapies. Herein, we evaluated efficacy and safety of splice factor-based treatments to correct mutation-induced splice defects in an <i>Opa1</i> mutant mouse line. We applied adeno-associated viruses to the retina. The viruses transduced retinal cells with an engineered U1 snRNA splice factor designed to correct the <i>Opa1</i> splice defect. We found the treatment to be efficient in increasing wild-type <i>Opa1</i> transcripts. Correspondingly, Opa1 protein levels increased significantly in treated eyes. Measurements of retinal morphology and function did not reveal therapy-related side-effects supporting the short-term safety of the treatment. Alterations of potential off-target genes were not detected. Our data suggest that treatments of splice defects applying engineered U1 snRNAs represent a promising in vivo therapeutic approach. The therapy increased wild-type <i>Opa1</i> transcripts and protein levels without detectable morphological, functional or genetic side-effects in the mouse eye. The U1 snRNA-based therapy can be tailored to specific disease gene mutations, hence, raising the possibility of a wider applicability of this promising technology towards treatment of different inherited retinal diseases.https://www.mdpi.com/2073-4409/12/6/955subretinal injectiongene therapyU1 snRNAU6 snRNAAAVsplice correction |
| spellingShingle | Sebastian Swirski Oliver May Malte Ahlers Bernd Wissinger Martin Greschner Christoph Jüschke John Neidhardt In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina Cells subretinal injection gene therapy U1 snRNA U6 snRNA AAV splice correction |
| title | In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina |
| title_full | In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina |
| title_fullStr | In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina |
| title_full_unstemmed | In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina |
| title_short | In Vivo Efficacy and Safety Evaluations of Therapeutic Splicing Correction Using U1 snRNA in the Mouse Retina |
| title_sort | in vivo efficacy and safety evaluations of therapeutic splicing correction using u1 snrna in the mouse retina |
| topic | subretinal injection gene therapy U1 snRNA U6 snRNA AAV splice correction |
| url | https://www.mdpi.com/2073-4409/12/6/955 |
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