title: VPAC2 receptor agonist BAY 55-9837 increases SMN protein levels and moderates disease phenotype in severe spinal muscular atrophy mouse models.
abstract: BACKGROUND
  Spinal Muscular Atrophy (SMA) is one of the most common inherited causes of infant death and is caused by the loss of functional survival motor neuron (SMN) protein due to mutations or deletion in the SMN1 gene. One of the treatment strategies for SMA is to induce the expression of the protein from the homologous SMN2 gene, a rescuing paralog for SMA.
  
  
  RESULTS
  Here we demonstrate the promise of pharmacological modulation of SMN2 gene by BAY 55-9837, an agonist of the vasoactive intestinal peptide receptor 2 (VPAC2), a member of G protein coupled receptor family. Treatment with BAY 55-9837 lead to induction of SMN protein levels via activation of MAPK14 or p38 pathway in vitro. Importantly, BAY 55-9837 also ameliorated disease phenotype in severe SMA mouse models.
  
  
  CONCLUSIONS
  Our findings suggest the VPAC2 pathway is a potential SMA therapeutic target.
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Hadwen
authors.forename: Duncan
authors.initials: D
authors.lastname: MacKenzie
authors.forename: Fahad
authors.initials: F
authors.lastname: Shamim
authors.forename: Kevin
authors.initials: K
authors.lastname: Mongeon
authors.forename: Martin
authors.initials: M
authors.lastname: Holcik
authors.affiliation: University of Ottawa, Ottawa K1H 8M5, Canada. MacKenzie@cheo.on.ca.
authors.forename: Alex
authors.initials: A
authors.lastname: MacKenzie
authors.forename: Faraz
authors.initials: F
authors.lastname: Farooq
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy*; D010446:Peptide Fragments / Q000627:therapeutic use*; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000819:agonists*; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism*; D014660:Vasoactive Intestinal Peptide / Q000627:therapeutic use
chemical_list: D010446:Peptide Fragments; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D055533:Survival of Motor Neuron 1 Protein; C409214:vasoactive intestinal peptide (1-7)-GRF (8-27), Lys(15)-Arg(16)-Leu(27)-; D014660:Vasoactive Intestinal Peptide