Development of Novel Screening Assays to Identify SMN2 Inducers
Target Investigator:
Matthew E. R. Butchbach, PhD
Head – Motor Neuron Diseases Research Laboratory
Mentor: Robert W Mason, Ph.D.

Proximal spinal muscular atrophy (SMA) is characterized by the loss of spinal motor neurons which leads to muscle weakness and atrophy. SMA results from the loss or mutation of SMN1 (survival motor neuron 1) but retention of its duplicate gene SMN2. SMN2 copy number variation is a major modifier of disease severity in SMA and is an ideal target for the identification and development of therapeutic strategies to increase levels of SMN protein for treatment of SMA. Previous screening of small molecule libraries for inducers of SMN2 expression have relied on reporter constructs that only use short regions of SMN2 to examine effects on the promoter or splicing and have not been designed to take full account of distal elements involved in the regulation of SMN2 expression. In this project, we will establish novel reporter cell lines to simultaneously monitor changes in both SMN2 promoter activity and inclusion of exon 7 in SMN2 transcripts in the context of the entire SMN2 genomic locus thereby more closely mimicking SMN2 gene regulation in vivo. These reporter constructs will be expressed in NSC-34 motor neuron-like cells—the primary cell type affected most severely affected in SMA. These novel reporter cell lines will be used to more accurately identify new small molecule regulators of SMN2 expression. Ultimately, this pilot project will lead to the development of better therapeutics for SMA patients.

SMN2 allele