Tetracyclines That Promote SMN2 Exon 7 Splicing as Therapeutics for Spinal Muscular Atrophy

Hastings, M. L., Berniac, J., Liu, Y. H., Abato, P., Jodelka, F. M., Barthel, L., Kumar, S., Dudley, C., Nelson, M., Larson, K., Edmonds, J., Bowser, T., Draper, M., Higgins, P., Krainer, A. R. (November 2009) Tetracyclines That Promote SMN2 Exon 7 Splicing as Therapeutics for Spinal Muscular Atrophy. Science Translational Medicine, 1 (5). ISSN 1946-6234

URL: http://www.ncbi.nlm.nih.gov/pubmed/20161659
DOI: 10.1126/scitranslmed.3000208

Abstract

There is at present no cure or effective therapy for spinal muscular atrophy (SMA), a neurodegenerative disease that is the leading genetic cause of infant mortality. SMA usually results from loss of the SMN1 (survival of motor neuron 1) gene, which leads to selective motor neuron degeneration. SMN2 is nearly identical to SMN1 but has a nucleotide replacement that causes exon 7 skipping, resulting in a truncated, unstable version of the SMA protein. SMN2 is present in all SMA patients, and correcting SMN2 splicing is a promising approach for SMA therapy. We identified a tetracycline-like compound, PTK-SMA1, which stimulates exon 7 splicing and increases SMN protein levels in vitro and in vivo in mice. Unlike previously identified molecules that stimulate SMN production via SMN2 promoter activation or undefined mechanisms, PTK-SMA1 is a unique therapeutic candidate in that it acts by directly stimulating splicing of exon 7. Synthetic small-molecule compounds such as PTK-SMA1 offer an alternative to antisense oligonucleotide therapies that are being developed as therapeutics for a number of disease-associated splicing defects.

Item Type: Paper
Uncontrolled Keywords: survival-motor-neuron pre-messenger-rna valproic acid increases gene-expression protein-level mouse model spliceosome disease target htra2-beta-1
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons > exon splicing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > exons
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > pre-mRNA
diseases & disorders > congenital hereditary genetic diseases > spinal muscular atrophy
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL Cancer Center Shared Resources > Animal Services
CSHL Cancer Center Shared Resources > Antibody and Phage Display Service
Depositing User: Matt Covey
Date: November 2009
Date Deposited: 11 Dec 2013 20:39
Last Modified: 29 Dec 2014 20:47
PMCID: PMC2818805
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28904

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