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Genes 2018, 9(9), 455; https://doi.org/10.3390/genes9090455

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

1
Research and Development Unit, Department of Human Genetics, INSA, 4000-055 Porto, Portugal
2
Neurology Service, Santo António Hospital, CHP, 4099-001 Porto, Portugal
*
Author to whom correspondence should be addressed.
Received: 3 July 2018 / Revised: 31 August 2018 / Accepted: 5 September 2018 / Published: 11 September 2018
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Abstract

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. View Full-Text
Keywords: antisense oligonucleotides; CSTB gene; progressive myoclonic epilepsy type 1; splicing mutation; splicing therapies antisense oligonucleotides; CSTB gene; progressive myoclonic epilepsy type 1; splicing mutation; splicing therapies
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).
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Matos, L.; Duarte, A.J.; Ribeiro, D.; Chaves, J.; Amaral, O.; Alves, S. Correction of a Splicing Mutation Affecting an Unverricht-Lundborg Disease Patient by Antisense Therapy. Genes 2018, 9, 455.

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