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

Jonathan J. Cherry, Erkan Y. Osman, Matthew C. Evans, Sungwoon Choi, Xuechao Xing, Gregory D. Cuny, Marcie A. Glicksman, Christian L. Lorson, Elliot J. Androphy

Research output: Contribution to journalArticle

33 Scopus citations


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. 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.

Original languageEnglish (US)
Pages (from-to)1103-1118
Number of pages16
JournalEMBO Molecular Medicine
Issue number7
StatePublished - Jul 2013



  • Drug discovery
  • SMA
  • SMN
  • SMN2
  • Spinal muscular atrophy

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Cherry, J. J., Osman, E. Y., Evans, M. C., Choi, S., Xing, X., Cuny, G. D., Glicksman, M. A., Lorson, C. L., & Androphy, E. J. (2013). Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds. EMBO Molecular Medicine, 5(7), 1103-1118. https://doi.org/10.1002/emmm.201202305