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

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

doi:10.1002/emmm.201202305

Abstract

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.

Highlights

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that presents as progressive muscle wasting and loss of motor function
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
SMA is primarily caused by the loss or mutation of both copies of the SMN1 gene

Summary

Introduction

Spinal muscular atrophy (SMA) is a neurodegenerative disorder that presents as progressive muscle wasting and loss of motor function. While the protein coding capacity of SMN2 is identical to that of SMN1 (Jablonka et al, 2000a), there is a translationally silent nucleotide variation in exon 7 of SMN2 (Lorson et al, 1999; Monani et al, 1999). This C to T transition results in alternative splicing of SMN2 and exclusion of exon 7. From the SMN2 mRNA, $85% of the messages lack exon 7 (Gavrilov et al, 1998; Gennarelli et al, 1995; Lorson et al, 1999; Monani et al, 1999) and express a truncated form of the protein (SMND7). The SMND7 protein is inactive and cannot fully compensate for the loss of SMN1 (Burnett et al, 2009; Lorson & Androphy, 2000; Lorson et al, 1998)

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