Hua, Y., Krainer, A. R. (2016) Antisense-Oligonucleotide Modulation of SMN2 Pre-mRNA Splicing. In: Spinal Muscular Atrophy: Disease Mechanisms and Therapy. Elsevier, pp. 301-311. ISBN 978-012803686-0978-012803685-3
Abstract
Loss-of-function mutations of the SMN1 gene, in the presence of its splicing-defective paralog, SMN2, cause spinal muscular atrophy (SMA). Both genes encode the essential survival motor neuron (SMN) protein; however, SMN2 predominantly expresses an unstable exon 7 skipped isoform (SMNδ7) due to a silent C to T nucleotide transition in exon 7. Targeting SMN2 splicing to increase full-length protein expression is a promising approach for therapeutic intervention. Antisense oligonucleotide (ASO) technology offers a precise tool to correct splicing. The splicing pattern of a pre-mRNA reflects the combinatorial interplay among multiple intronic and exonic splicing enhancers and silencers, bound by various splicing activators and repressors, respectively. ASO basepairing to pre-mRNA can potentially block repressor binding, promoting exon inclusion. We systematically screened many ASOs with overlapping complementarity to SMN2 pre-mRNA along exon 7 and introns 6 and 7. An optimal 18mer ASO, designated ASO10-27 or ISIS-SMNRx, promotes efficient exon 7 inclusion in vivo. ISIS-SMNRx-renamed nusinersen-underwent extensive preclinical characterization and is currently in pivotal phase-3 clinical trials involving intrathecal administration in SMA infants and children. © 2017 Elsevier Inc. All rights reserved.
| Item Type: | Book Section |
|---|---|
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNA splicing |
| CSHL Authors: | |
| Communities: | CSHL labs > Krainer lab |
| Depositing User: | Matt Covey |
| Date: | 2016 |
| Date Deposited: | 23 Aug 2017 15:57 |
| Last Modified: | 23 Aug 2017 15:57 |
| URI: | https://repository.cshl.edu/id/eprint/35256 |
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