Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds. Issue 7 (5th June 2013)

• Record Type: Journal Article
• Authors: Cherry, Jonathan J.; Osman, Erkan Y.; Evans, Matthew C.; Choi, Sungwoon; Xing, Xuechao; Cuny, Gregory D.; Glicksman, Marcie A.; Lorson, Christian L.; Androphy, Elliot J.
• Is Part Of: EMBO molecular medicine. Volume 5:Issue 7(2013:Jul.)
• Page Start: 1103
• Page End: 1118
• Publication Date: 2013-06-05
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201202305
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" xml:lang="en"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="emmm201202305-sec-0001" sec-type="section"> <p>Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the <italic>SMN1</italic> gene. <italic>SMN2</italic> is a nearly identical copy of <italic>SMN1</italic>, which expresses much less functional SMN protein. <italic>SMN2</italic> is unable to fully compensate for the loss of <italic>SMN1</italic> in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full‐length SMN protein from the endogenous <italic>SMN2</italic> gene should lessen disease severity. We have developed and implemented a new high‐throughput screening assay to identify small molecules that increase the expression of full‐length SMN from a <italic>SMN2</italic> reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.</p> </sec> </abstract>