Targeting epigenetic proteins to treat Spinal Muscular Atrophy

Spinal Muscular Atrophy is a neuromuscular disorder and leading genetic cause of infant mortality. It is caused by the loss of Survival Motor Neuron 1 (SMN1) gene encoding SMN1 protein, leading to death of motor neurons. The most prevalent type of SMA, Type I, presents itself before 6 months of age, leads to muscle weakness, and death typically before the age of two. Recent FDA approval of Spinraza for the treatment of SMA has given hope that this natural history will soon become radically different. However Spinraza, an antisense oligonucleotide targeting the splicing of SMN2, has its limitations. It is focused only towards the CNS, highly costly, and its' benefits are mainly seen in the most severe patients. In contrast, small molecule which can be given orally and provide neuroprotective effects in SMA patients would offer a more refined and potentially safer option of treatment. A promising target for small molecules are epigenetic proteins. Epigenetic proteins are involved in neuroprotective responses for Huntington's and Parkinson's diseases and regulation of SMN has been shown to be influenced by epigenetic modifiers. The Structural Genomic Consortium (SGC) is a group in Oxford has developed a series of novel chemical probes which inhibit or antagonize proteins involved in epigenetic signalling. We propose to screen these small molecules for activation of SMN expression as well as their effect on proliferation, differentiation and cell survival in cultured neuroblastoma and SMA iPSC-derived motor neurons. Successful molecules will be further analysed in a mouse model for SMA individually and in combination with antisense oligonucleotide treatment. The primary aim of the project is to identify novel small molecule(s) targeting epigenetic regulator mechanisms to treat SMA through SMN and non-SMN dependent pathways.