title: Omigapil ameliorates the pathology of muscle dystrophy caused by laminin-alpha2 deficiency.
abstract: Laminin alpha2-deficient congenital muscular dystrophy, called MDC1A, is a rare, devastating genetic disease characterized by severe neonatal hypotonia ("floppy infant syndrome"), peripheral neuropathy, inability to stand or walk, respiratory distress, and premature death in early life. Transgenic overexpression of the apoptosis inhibitor protein BCL-2, or deletion of the proapoptotic Bax gene in a mouse model for MDC1A prolongs survival and mitigates pathology, indicating that apoptotic events are involved in the pathology. Here we demonstrate that the proapoptotic glyceraldehyde-3-phosphate dehydrogenase (GAPDH)-Siah1-CBP/p300-p53 pathway is activated in a mouse model for MDC1A. Moreover, we show that omigapil, which inhibits GAPDH-Siah1-mediated apoptosis, ameliorates several pathological hallmarks in the MDC1A mouse model. Specifically, we demonstrate that treatment with omigapil inhibits apoptosis in muscle, reduces body weight loss and skeletal deformation, increases locomotive activity, and protects from early mortality. These data qualify omigapil, which is in late phase of clinical development for human use, as a drug candidate for the treatment of MDC1A.
authors.affiliation: Santhera Pharmaceuticals, Liestal, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Erb
authors.forename: Sarina
authors.initials: S
authors.lastname: Meinen
authors.forename: Patrizia
authors.initials: P
authors.lastname: Barzaghi
authors.forename: Lazar T
authors.initials: LT
authors.lastname: Sumanovski
authors.forename: Isabelle
authors.initials: I
authors.lastname: Courdier-Früh
authors.forename: Markus A
authors.initials: MA
authors.lastname: Rüegg
authors.forename: Thomas
authors.initials: T
authors.lastname: Meier
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D007797:Laminin / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D009687:Nuclear Proteins / Q000378:metabolism; D010082:Oxepins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000378:metabolism; D000098563:Seven in Absentia Proteins
chemical_list: D007797:Laminin; D009687:Nuclear Proteins; D010082:Oxepins; D016159:Tumor Suppressor Protein p53; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; C102645:laminin alpha 2; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D050880:p300-CBP Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins