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Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy

Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To over...

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Autores principales: Matos, Liliana, Duarte, Ana Joana, Ribeiro, Diogo, Chaves, João, Amaral, Olga, Alves, Sandra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162617/
https://www.ncbi.nlm.nih.gov/pubmed/30208654
http://dx.doi.org/10.3390/genes9090455
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author Matos, Liliana
Duarte, Ana Joana
Ribeiro, Diogo
Chaves, João
Amaral, Olga
Alves, Sandra
author_facet Matos, Liliana
Duarte, Ana Joana
Ribeiro, Diogo
Chaves, João
Amaral, Olga
Alves, Sandra
author_sort Matos, Liliana
collection PubMed
description Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5′ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases.
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spelling pubmed-61626172018-10-10 Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy Matos, Liliana Duarte, Ana Joana Ribeiro, Diogo Chaves, João Amaral, Olga Alves, Sandra Genes (Basel) Brief Report Unverricht-Lundborg disease (ULD) is a common form of progressive myoclonic epilepsy caused by mutations in the cystatin B gene (CSTB) that encodes an inhibitor of several lysosomal cathepsins. Presently, only pharmacological treatment and psychosocial support are available for ULD patients. To overcome the pathogenic effect of the ULD splicing mutation c.66G>A (exon 1), we investigated whether an antisense oligonucleotide therapeutic strategy could correct the defect in patient cells. A specific locked nucleic acid (LNA) antisense oligonucleotide was designed to block a cryptic 5′ss in intron 1. Overall, this approach allowed the restoration of the normal splicing pattern. Furthermore, the recovery was both sequence and dose-specific. In general, this work provides a proof of principle on the correction of a CSTB gene defect causing ULD through a mutation-specific antisense therapy. It adds evidence to the feasibility of this approach, joining the many studies that are paving the way for translating antisense technology into the clinical practice. The insights detailed herein make mutation-based therapy a clear candidate for personalized treatment of ULD patients, encouraging similar investigations into other genetic diseases. MDPI 2018-09-11 /pmc/articles/PMC6162617/ /pubmed/30208654 http://dx.doi.org/10.3390/genes9090455 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Matos, Liliana
Duarte, Ana Joana
Ribeiro, Diogo
Chaves, João
Amaral, Olga
Alves, Sandra
Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
title Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
title_full Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
title_fullStr Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
title_full_unstemmed Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
title_short Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
title_sort correction of a splicing mutation affecting an unverricht-lundborg disease patient by antisense therapy
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162617/
https://www.ncbi.nlm.nih.gov/pubmed/30208654
http://dx.doi.org/10.3390/genes9090455
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