Towards correction of splicing defects through application of mutation-specific splice factors in vivo.

We aim to develop a gene therapy that applies designed splice factors to correct mutation-induced splicing deficits. Splice site mutations are frequently identified in monogenetic diseases: about 10 % of all disease-associated mutations affect mRNA splicing. We make use of a mouse model that is affected by a splice donor site mutation in a gene associated with retinal degeneration. Phenotypically, the mice show an early-onset, slow degeneration of rod and cone photoreceptor cells. On the molecular level, the gene defect, i.e. splice donor site mutation, leads to skipping of an exon resulting in a non-functional protein. We designed mutation-adapted splice factors that are able to recognize mutated splice sites and consequently silence the effect of the mutation. Our initial data are promising and support that the approach is effective in vivo following the application of an AAV that mediates the expression of our designed splice factors in the retina. The future plans of the project include the evaluation of efficacy and safety of the 'designed splice factor approach' in mice.

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