Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption

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 pa...

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Autores principales:	Christoph Jüschke, Thomas Klopstock, Claudia B. Catarino, Marta Owczarek-Lipska, Bernd Wissinger, John Neidhardt
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	gene therapy U1 snRNA ExSpeU1 splicing Dominant Optic Atrophy DOA Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a11ea567c94342c38da3cd307ffe83ad
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spelling	oai:doaj.org-article:a11ea567c94342c38da3cd307ffe83ad2021-11-18T04:47:43ZAutosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption2162-253110.1016/j.omtn.2021.10.019https://doaj.org/article/a11ea567c94342c38da3cd307ffe83ad2021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2162253121002626https://doaj.org/toc/2162-2531Autosomal 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.Christoph JüschkeThomas KlopstockClaudia B. CatarinoMarta Owczarek-LipskaBernd WissingerJohn NeidhardtElsevierarticlegene therapyU1 snRNAExSpeU1splicingDominant Optic AtrophyDOATherapeutics. PharmacologyRM1-950ENMolecular Therapy: Nucleic Acids, Vol 26, Iss , Pp 1186-1197 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	gene therapy U1 snRNA ExSpeU1 splicing Dominant Optic Atrophy DOA Therapeutics. Pharmacology RM1-950
spellingShingle	gene therapy U1 snRNA ExSpeU1 splicing Dominant Optic Atrophy DOA Therapeutics. Pharmacology RM1-950 Christoph Jüschke Thomas Klopstock Claudia B. Catarino Marta Owczarek-Lipska Bernd Wissinger John Neidhardt Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption
description	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.
format	article
author	Christoph Jüschke Thomas Klopstock Claudia B. Catarino Marta Owczarek-Lipska Bernd Wissinger John Neidhardt
author_facet	Christoph Jüschke Thomas Klopstock Claudia B. Catarino Marta Owczarek-Lipska Bernd Wissinger John Neidhardt
author_sort	Christoph Jüschke
title	Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption
title_short	Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption
title_full	Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption
title_fullStr	Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption
title_full_unstemmed	Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption
title_sort	autosomal dominant optic atrophy: a novel treatment for opa1 splice defects using u1 snrna adaption
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/a11ea567c94342c38da3cd307ffe83ad
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Autosomal dominant optic atrophy: A novel treatment for OPA1 splice defects using U1 snRNA adaption

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