Repair of Rhodopsin mRNA by Spliceosome-Mediated RNA Trans-Splicing: A New Approach for Autosomal Dominant Retinitis Pigmentosa

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.  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 (RP).  Retinitis pigmentosa is characterized by a progressive degeneration of rod photoreceptors, leading to night-blindness and constriction of the visual field, followed by the degeneration of cone photoreceptors, resulting in a total loss of vision.  In this study, we demonstrated the repair of dominant mutations of RHO by RNA trans-splicing. Using two different cellular models of RHO expression, we showed that a significant proportion—up to 40%—of the mRNA could be repaired, leading to an improvement of the phenotype, characterized by correction of the subcellular distribution of RHO.

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