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Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy

Marrosu, E; Ala, P; Muntoni, F; Zhou, H; (2017) Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy. Molecular Therapy - Nucleic Acids , 8 pp. 416-427. 10.1016/j.omtn.2017.07.006. Green open access

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Abstract

Dominant-negative mutations in the genes that encode the three major a chains of collagen type VI, COL6A1, COL6A2, and COL6A3, account for more than 50% of Ullrich congenital muscular dystrophy patients and nearly all Bethlem myopathy patients. Gapmer antisense oligonucleotides (AONs) are usually used for gene silencing by stimulating RNA cleavage through the recruitment of an endogenous endonuclease known as RNase H to cleave the RNA strand of a DNA-RNA duplex. In this study, we exploited the application of the allele-specific silencing approach by gapmer AON as a potential therapy for Collagen-VI-related congenital muscular dystrophy (COL6-CMD). A series of AONs were designed to selectively target an 18-nt heterozygous genomic deletion in exon 15 of COL6A3 at the mRNA and pre-mRNA level. We showed that gapmer AONs can selectively suppress the expression of mutant transcripts at both pre-mRNA and mRNA levels, and that the latter strategy had a far stronger efficiency than the former. More importantly, we found that silencing of the mutant transcripts by gapmer AONs increased the deposition of collagen VI protein into the extracellular matrix, thus restoring functional protein production. Our findings provide a clear proof of concept for AON allele-specific silencing as a therapeutic approach for COL6-CMD

Type: Article
Title: Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omtn.2017.07.006
Publisher version: http://doi.org/10.1016/j.omtn.2017.07.006
Language: English
Additional information: © 2017 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Science & Technology, Life Sciences & Biomedicine, Medicine, Research & Experimental, Research & Experimental Medicine, VI-RELATED MYOPATHIES, COLLAGEN-VI, NEUROMUSCULAR DISEASE, NATURAL-HISTORY, DOSE-ESCALATION, GENE-EXPRESSION, OPEN-LABEL, RNASE H1, FIBROBLASTS, DOMINANT, collagen VIcongenital muscular dystrophydominant mutationsantisense oligonucleotide therapygapmerallele-specific silencing
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Developmental Neurosciences Prog
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Genetics and Genomic Medicine Prog
URI: http://discovery.ucl.ac.uk/id/eprint/1571629
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