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Science. 2014 Aug 8;345(6197):688-93. doi: 10.1126/science.1250127.

Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy.

Author information

1
PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA.
2
Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA.
3
PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. friedrich.metzger@roche.com speltz@ptcbio.com.
4
SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA.
5
Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
6
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland.
7
Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. friedrich.metzger@roche.com speltz@ptcbio.com.

Abstract

Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Δ7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.

PMID:
25104390
DOI:
10.1126/science.1250127
[Indexed for MEDLINE]
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