Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: Towards a treatment for spinal muscular atrophy

E. Buratti; C. Mitrpant; P. Porensky; H. Zhou; L. Price; F. Muntoni; S. Fletcher; S.D. Wilton; A.H.M. Burghes

doi:10.1371/journal.pone.0062114

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Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: Towards a treatment for spinal muscular atrophy

Journal article

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Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: Towards a treatment for spinal muscular atrophy

E. Buratti, C. Mitrpant, P. Porensky, H. Zhou, L. Price, F. Muntoni, S. Fletcher, S.D. Wilton and A.H.M. Burghes

PLoS ONE, Vol.8(4), e62114

2013

DOI: https://doi.org/10.1371/journal.pone.0062114

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Abstract

Spinal muscular atrophy (SMA) is caused by loss of the Survival Motor Neuron 1 (SMN1) gene, resulting in reduced SMN protein. Humans possess the additional SMN2 gene (or genes) that does produce low level of full length SMN, but cannot adequately compensate for loss of SMN1 due to aberrant splicing. The majority of SMN2 gene transcripts lack exon 7 and the resultant SMNΔ7 mRNA is translated into an unstable and non-functional protein. Splice intervention therapies to promote exon 7 retention and increase amounts of full-length SMN2 transcript offer great potential as a treatment for SMA patients. Several splice silencing motifs in SMN2 have been identified as potential targets for antisense oligonucleotide mediated splice modification. A strong splice silencer is located downstream of exon 7 in SMN2 intron 7. Antisense oligonucleotides targeting this motif promoted SMN2 exon 7 retention in the mature SMN2 transcripts, with increased SMN expression detected in SMA fibroblasts. We report here systematic optimisation of phosphorodiamidate morpholino oligonucleotides (PMO) that promote exon 7 retention to levels that rescued the phenotype in a severe mouse model of SMA after intracerebroventricular delivery. Furthermore, the PMO gives the longest survival reported to date after a single dosing by ICV.

Details

Title: Improved antisense oligonucleotide design to suppress aberrant SMN2 gene transcript processing: Towards a treatment for spinal muscular atrophy
Authors/Creators: E. Buratti (Author/Creator)
C. Mitrpant (Author/Creator) - The University of Western Australia
P. Porensky (Author/Creator) - The Ohio State University Wexner Medical Center
H. Zhou (Author/Creator) - Great Ormond Street Hospital
L. Price (Author/Creator) - The University of Western Australia
F. Muntoni (Author/Creator) - Great Ormond Street Hospital
S. Fletcher (Author/Creator) - The University of Western Australia
S.D. Wilton (Author/Creator) - The University of Western Australia
A.H.M. Burghes (Author/Creator) - The Ohio State University Wexner Medical Center
Publication Details: PLoS ONE, Vol.8(4), e62114
Publisher: Public Library of Science
Identifiers: 991005542787307891
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.2204 Spinal Muscular Atrophy
Web Of Science research areas: Genetics & Heredity
ESI research areas: Molecular Biology & Genetics