title: Treatment with selumetinib preserves cardiac function and improves survival in cardiomyopathy caused by mutation in the lamin A/C gene.
abstract: OBJECTIVE
  Mutations in A-type nuclear lamins gene, LMNA, lead to a dilated cardiomyopathy. We have reported abnormal activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signalling in hearts from Lmna(H222P/H222P) mice, which develop dilated cardiomyopathy. We therefore determined whether an inhibitor of ERK1/2 signalling that has been investigated in clinical trials for cancer has the potential to be translated to humans with LMNA cardiomyopathy.
  
  
  RESULTS
  To evaluate the relevance of this finding in mice to patients, we analysed the ERK1/2 signalling in heart tissue from human subjects with LMNA cardiomyopathy and showed that it was abnormally activated. To determine whether pharmacological inhibitors of the ERK1/2 signalling pathway could potentially be used to treat LMNA cardiomyopathy, we administered selumetinib to male Lmna(H222P/H222P) mice starting at 16 weeks of age, after they show signs of cardiac deterioration, up to 20 weeks of age. Selumetinib is an inhibitor of ERK1/2 signalling and has been given safely to human subjects in clinical trials for cancer. Systemic treatment with selumetinib inhibited cardiac ERK1/2 phosphorylation and blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere architecture that occurred in placebo-treated mice. Echocardiography and histological analysis demonstrated that treatment increases cardiac fractional shortening, prevents myocardial fibrosis, and prolongs survival. Selumetinib treatment did not induce biochemical abnormalities suggestive of renal or hepatic toxicity.
  
  
  CONCLUSIONS
  Our results suggest that selumetinib or other related inhibitors that have been safely administered to humans in clinical trials could potentially be used to treat LMNA cardiomyopathy.
authors: Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10th Floor, Room 508, New York, NY 10032, USA. am2434@columbia.edu
authors: Antoine
authors: A
authors: Muchir
authors: Sarah A
authors: SA
authors: Reilly
authors: Wei
authors: W
authors: Wu
authors: Shinichi
authors: S
authors: Iwata
authors: Shunichi
authors: S
authors: Homma
authors: Gisèle
authors: G
authors: Bonne
authors: Howard J
authors: HJ
authors: Worman
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use* / Q000633:toxicity; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006321:Heart / Q000503:physiopathology*; D006801:Humans; D007668:Kidney / Q000187:drug effects; D034904:Lamin Type A / Q000235:genetics*; D008099:Liver / Q000187:drug effects; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D010179:Pancreas / Q000187:drug effects
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D034904:Lamin Type A; C440308:lamin C; D048049:Extracellular Signal-Regulated MAP Kinases