Open AccessEnhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug‐like compounds
Author(s) -
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.
Publication year - 2013
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.1002/emmm.201202305
Subject(s) - smn1 , spinal muscular atrophy , sma* , biology , gene , microbiology and biotechnology , cancer research , genetics , mathematics , combinatorics
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.