Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds

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 SMN1 gene. SMN2 is a nearly identical copy of SMN1 , which expresses much less functiona...

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Veröffentlicht in:EMBO molecular medicine 2013-07, Vol.5 (7), p.1103-1118
Hauptverfasser: 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.
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Sprache:eng
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Zusammenfassung: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 SMN1 gene. SMN2 is a nearly identical copy of SMN1 , which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full‐length SMN protein from the endogenous SMN2 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 SMN2 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. Graphical Abstract Spinal muscular atrophy (SMA) is caused by loss of SMN and is one of the leading heritable causes of infant death. The Authors describe new small molecules that increase SMN levels leading to improved lifespan and motor function in a SMA mouse model.
ISSN:1757-4676
1757-4684
DOI:10.1002/emmm.201202305