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Recent Advances and Clinical Applications of Exon Inclusion for Spinal Muscular Atrophy.
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- Author(s): Son HW;Son HW; Yokota T; Yokota T; Yokota T
- Source:
Methods in molecular biology (Clifton, N.J.) [Methods Mol Biol] 2018; Vol. 1828, pp. 57-68.
- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't; Review
- Language:
English
- Additional Information
- Source:
Publisher: Humana Press Country of Publication: United States NLM ID: 9214969 Publication Model: Print Cited Medium: Internet ISSN: 1940-6029 (Electronic) Linking ISSN: 10643745 NLM ISO Abbreviation: Methods Mol Biol Subsets: MEDLINE
- Publication Information:
Publication: Totowa, NJ : Humana Press
Original Publication: Clifton, N.J. : Humana Press,
- Subject Terms:
- Abstract:
Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in SMN1 that stops production of SMN (survival of motor neuron) protein. Insufficient levels of SMN results in the loss of motor neurons, which causes muscle weakness, respiratory distress, and paralysis. A nearly identical gene (SMN2) contains a C-to-T transition which excludes exon 7 from 90% of the mature mRNA transcripts, leading to unstable proteins which are targeted for degradation. Although SMN2 cannot fully compensate for a loss of SMN1 due to only 10% functional mRNA produced, the discovery of the intronic splicing silencer (ISS-N1) opened a doorway for therapy. By blocking its function with antisense oligonucleotides manipulated for high specificity and efficiency, exon 7 can be included to produce full-length mRNA, which then compensates for the loss of SMN1. Nusinersen (Spinraza), the first FDA-approved antisense oligonucleotide drug targeting SMA, was designed based on this concept and clinical studies have demonstrated a dramatic improvement in patients. Novel chemistries including phosphorodiamidate morpholino oligomers (PMOs) and locked nucleic acids (LNAs), as well as peptide conjugates such as Pip that facilitate accurate targeting to the central nervous system, are explored to increase the efficiency of exon 7 inclusion in the appropriate tissues to ameliorate the SMA phenotype. Due to the rapid advancement of treatments for SMA following the discovery of ISS-N1, the future of SMA treatment is highly promising.
- Grant Information:
Canada CIHR
- Contributed Indexing:
Keywords: Antisense oligonucleotides; Antisense therapy; Dubowitz disease; Exon inclusion; Kugelberg–Welander disease; Morpholino; Nusinersen (Spinraza); Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO); Phosphorodiamidate morpholino oligomer (PMO); Spinal muscular atrophy (SMA); Werdnig–Hoffmann disease
- Accession Number:
0 (Oligonucleotides, Antisense)
- Publication Date:
Date Created: 20180902 Date Completed: 20190401 Latest Revision: 20190401
- Publication Date:
20221213
- Accession Number:
10.1007/978-1-4939-8651-4_3
- Accession Number:
30171534
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