Spinal muscular atrophy (SMA) is a leading genetic cause of infant death in the world. SMA is the result of reduced expression of SMN protein. In humans there are two nearly identical copies of the SMN gene (SMN1 and SMN2). There is a C-T transition in exon 7 of SMN2 that alters a splicing regulatory element which leads to reduced inclusion of exon 7 in SMN2-derived transcripts and, hence, reduced levels of SMN protein. In SMA, SMN1 (which produces full-length SMN protein) is lost while SMN2 is retained. SMN gene replacement using gene therapy vectors and modulation of SMN expression by drug compounds have been shown to improve the survival and phenotypes of various mouse models of SMA.
Studies using transgenic mice have shown that increasing SMN2 copy number improves the survival and phenotype of SMA mouse models. Likewise, in humans, patients with a higher the SMN2 copy number generally have the milder the SMA phenotype. These observations collectively suggest that SMN2 may be a therapeutic target for SMA. In this project, we will generate novel methods to monitor SMN2 induction and exon 7 inclusion in the spinal cord of living SMA mice. This information will be extremely useful in understanding the effectiveness of SMN-inducing drugs in treating SMA and will lead to the design of newer drugs with better protective properties.
Butyrate-based compounds such as phenylbutyrate have been suggested to be potential drug compounds for treating SMA patients. These compounds improve survival of a mouse model of SMA but do not increase SMN in the spinal cord. Work from others has shown that administration of 4-phenylbutyrate to SOD1(G93A) amyotrophic lateral sclerosis (ALS) transgenic mice improves their survival by ~21%. In this project, we propose to test butyrate-based compounds in transgenic mouse models for motor neuron diseases such as SMA, ALS and SMA with respiratory distress 1 (SMARD1). We will also determine the mechanism(s) by which these compounds exert their neuroprotective effects. These compounds, therefore, will be more potent therapeutics for motor neuron diseases which can be moved forward into clinical trials.