Journal Article

DZNE-2022-00417

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption.

Jüschke, C. ; Klopstock, T.DZNE* ; Catarino, C. B. ; Owczarek-Lipska, M. ; Wissinger, B. ; Neidhardt, J.

2021
Nature Publ. Group New York, NY

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Please use a persistent id in citations: doi:10.1016/j.omtn.2021.10.019

Abstract: Autosomal dominant optic atrophy (ADOA) is frequently caused by mutations in the optic atrophy 1 (OPA1) gene, with haploinsufficiency being the major genetic pathomechanism. Almost 30% of the OPA1-associated cases suffer from splice defects. We identified a novel OPA1 mutation, c.1065+5G>A, in patients with ADOA. In patient-derived fibroblasts, the mutation led to skipping of OPA1 exon 10, reducing the OPA1 protein expression by approximately 50%. We developed a molecular treatment to correct the splice defect in OPA1 using engineered U1 splice factors retargeted to different locations in OPA1 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 OPA1 transcripts may suffice to overcome the haploinsufficiency.

Keyword(s): ADOA ; Autosomal Dominant Optic Atrophy ; DOA ; Dominant Optic Atrophy ; ExSpeU1 ; OPA1 ; Optic Atrophy Type 1 ; U1 snRNA ; gene therapy ; splicing

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Contributing Institute(s):

1. Coordinator of Clinical Parkinson Research (AG Höglinger 2)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2021

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