ArticleMolecular therapy : the journal of the American Society of Gene Therapy2015
Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 77 citations in OpenAlex.
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- Fine-tuning FAM161A gene augmentation therapy to restore retinal function.EMBO molecular medicine · 2024Article
- Repurposing CRISPR-Cas13 systems for robust mRNA trans-splicing.Nature communications · 2024Article
- Programmable RNA writing with trans-splicing.bioRxiv : the preprint server for biology · 2024Article
- Gene augmentation therapy attenuates retinal degeneration in a knockout mouse model of Fam161a retinitis pigmentosa.Molecular therapy : the journal of the American Society of Gene Therapy · 2023Article
- Alternative RNA Splicing in the Retina: Insights and Perspectives.Cold Spring Harbor perspectives in medicine · 2023Review
- Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory.PLoS biology · 2023Article
- Pannexin 1 activity in astroglia sets hippocampal neuronal network patterns.PLoS biology · 2022Article
- Splicing mutations in the CFTR gene as therapeutic targets.Gene therapy · 2022Review
- Physiological synaptic activity and recognition memory require astroglial glutamine.Nature communications · 2022Article
- Clinical and genetic approach to renal hypomagnesemia.Biomedical journal · 2022Review
- Time-Course of Alterations in the Endocannabinoid System after Viral-Mediated Overexpression of α-Synuclein in the Rat Brain.Molecules (Basel, Switzerland) · 2022Article
- The Small Molecule Alpha-Synuclein Aggregator, FN075, Enhances Alpha-Synuclein Pathology in Subclinical AAV Rat Models.Biomolecules · 2021Article
Corrections and comments
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Authors and funding
9 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The promising clinical results obtained for ocular gene therapy in recent years have paved the way for gene supplementation to treat recessively inherited forms of retinal degeneration. The situation is more complex for dominant mutations, as the toxic mutant gene product must be removed. We used spliceosome-mediated RNA trans-splicing as a strategy for repairing the transcript of the rhodopsin gene, the gene most frequently mutated in autosomal dominant retinitis pigmentosa. We tested 17 different molecules targeting the pre-mRNA intron 1, by transient transfection of HEK-293T cells, with subsequent trans-splicing quantification at the transcript level. We found that the targeting of some parts of the intron promoted trans-splicing more efficiently than the targeting of other areas, and that trans-splicing rate could be increased by modifying the replacement sequence. We then developed cell lines stably expressing the rhodopsin gene, for the assessment of phenotypic criteria relevant to the pathogenesis of retinitis pigmentosa. Using this model, we showed that trans-splicing restored the correct localization of the protein to the plasma membrane. Finally, we tested our best candidate by AAV gene transfer in a mouse model of retinitis pigmentosa that expresses a mutant allele of the human rhodopsin gene, and demonstrated the feasibility of trans-splicing in vivo. This work paves the way for trans-splicing gene therapy to treat retinitis pigmentosa due to rhodopsin gene mutation and, more generally, for the treatment of genetic diseases with dominant transmission.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.