T.P.8 Induction of SMN protein by combination of STAT5 and p38 kinase activating, clinic ready compounds for the treatment of SMA

Abstract Spinal muscle atrophy (SMA) is an autosomal recessive neurodegenerative disease which is characterized by the loss of α motor neurons resulting in progressive muscle atrophy. Loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene is the cause of SMA. A potential treatment strategy for SMA is to upregulate levels SMN protein originating from the SMN2 gene compensating in part for the absence of functional SMN1 gene. Sodium valproate, TSA and aclarubicin, which effectively enhance SMN2 expression, have been shown to activate STAT5 in vitro. Given that Prolactin is also known to activate the STAT5 signalling pathway, we elected to assess its impact on SMN levels. In this manner we have demonstrated a significant induction in SMN levels in vitro upon treatment with Prolactin. We have demonstrated that activation of STAT5 pathway by Prolactin is necessary for this transcriptional upregulation of SMN gene. We have found that Prolactin treatment induces SMN expression, improves motor neuron function, ameliorates disease phenotype and increases survival in SMAΔ7 mice. We have previously documented that activation of p38 pathway stabilizes and increase SMN mRNA levels in vitro. We have identified and demonstrated a significant induction in SMN protein levels upon treatment with various clinic ready compounds which also activates p38 pathway. The impact of these compounds along with Prolactin on SMA mouse model is currently under investigation. This study will help in the identification and characterization of combination of potential therapeutic compounds for the treatment of SMA.