Antisense-Oligonucleotide Modulation of SMN2 Pre-mRNA Splicing

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

DOI: 10.1016/B978-0-12-803685-3.00018-5


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

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