Mitrpant, C;
Porensky, P;
Zhou, H;
Price, L;
Muntoni, F;
Fletcher, S;
Wilton, SD;
(2013)
Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy.
PLoS One
, 8
(4)
, Article e62114. 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.
| Type: | Article |
|---|---|
| Title: | Improved Antisense Oligonucleotide Design to Suppress Aberrant SMN2 Gene Transcript Processing: Towards a Treatment for Spinal Muscular Atrophy. |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1371/journal.pone.0062114 |
| Publisher version: | http://dx.doi.org/10.1371/journal.pone.0062114 |
| Language: | English |
| Additional information: | © 2013 Mitrpant et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the National Institutes of Health R01 HD060586 (AHMB), RC2 NS069476 (AHMB), AFM/SMA Europe (SDW), the Spinal Muscular Atrophy Association of Australia and the Parry Foundation of Australia (SDW) and Thailand Research Fund MRG5580095 (CM), UCL Therapeutic Innovation Fund, the Wellcome Trust Institutional Strategic Support Fund (Grant reference 097815/Z/11/Z) and UCL Biomedical Research Centre (Grant reference CBRC 161), and the Wellcome Trust Value in People awarded grant to HZ (Grant code FPEG). PP was supported by the Department of Neurosurgery residency program at Ohio State University. CM was supported by a Chalermprakiat grant from Faculty of Medicine, Siriraj Hospital, Mahidol University. FM is supported by Great Ormond Street Hospital Children's Charity and the ICH/GOSH Biomedical Research Centre. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. |
| UCL classification: | UCL 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 Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1392555 |
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