Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy
| Autor: | Olga Amaral, Diogo Ribeiro, Liliana Matos, Ana Joana Duarte, Sandra Alves, João Chaves |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
lcsh:QH426-470 government.form_of_government Genética Humana Progressive myoclonus epilepsy Bioinformatics medicine.disease_cause splicing mutation 03 medical and health sciences Exon 0302 clinical medicine CSTB gene Antisense Technology Genetics medicine progressive myoclonic epilepsy type 1 Genetics (clinical) Antisense therapy Mutation business.industry Brief Report splicing therapies Intron medicine.disease Doenças Genéticas Unverricht–Lundborg disease lcsh:Genetics 030104 developmental biology RNA splicing government antisense oligonucleotides business 030217 neurology & neurosurgery |
| Zdroj: | Genes Genes, Vol 9, Iss 9, p 455 (2018) Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) Agência para a Sociedade do Conhecimento (UMIC)-FCT-Sociedade da Informação instacron:RCAAP |
| ISSN: | 2073-4425 |
| Popis: | 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. This work was funded by FCT (Fundação para a Ciência e a Tecnologia—MCTES, Portugal) project PTDC/BBB-BMD/6301/2014. Liliana Matos was grant recipient from FCT under the same project info:eu-repo/semantics/publishedVersion |
| Databáze: | OpenAIRE |
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