Autosomal dominant optic atrophy: A novel treatment for splice defects using U1 snRNA adaption.

Autosomal dominant optic atrophy (ADOA) is frequently caused by mutations in the optic atrophy 1 () gene, with haploinsufficiency being the major genetic pathomechanism. Almost 30% of the -associated cases suffer from splice defects. We identified a novel mutation, c.1065+5G>A, in patients with ADOA. In patient-derived fibroblasts, the mutation led to skipping of exon 10, reducing the OPA1 protein expression by approximately 50%. We developed a molecular treatment to correct the splice defect in using engineered U1 splice factors retargeted to different locations in exon 10 or intron 10. The strongest therapeutic effect was detected when U1 binding was engineered to bind to intron 10 at position +18, a position predicted by bioinformatics to be a promising binding site. We were able to significantly silence the effect of the mutation (skipping of exon 10) and simultaneously increase the expression level of normal transcripts. Retargeting U1 to the canonical splice donor site did not lead to a detectable splice correction. This proof-of-concept study indicates for the first time the feasibility of splice mutation correction as a treatment option for ADOA. Increasing the amount of correctly spliced transcripts may suffice to overcome the haploinsufficiency.