title: Omigapil treatment decreases fibrosis and improves respiratory rate in dy(2J) mouse model of congenital muscular dystrophy.
abstract: BACKGROUND
  Congenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients.
  
  
  METHODS
  dy(2J) mice were treated with vehicle, 0.1 mg/kg or 1 mg/kg of omigapil daily via oral gavage over 17.5 weeks. Untreated age matched BL6 mice were used as controls. Functional, behavioral and histological measurements were collected.
  
  
  RESULTS
  dy(2J) mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy(2J) mice (396 to 402 vs. 371 breaths per minute, p<0.03) and similar to control mice. There were no statistical differences in normalized forelimb grip strength between dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups. At 30-33 weeks of age, dy(2J) mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy(2J) mice showed normal cardiac systolic function throughout the trial. dy(2J) mice had significantly lower hindlimb maximal (p<0.001) and specific force (p<0.002) compared to the control group at the end of the trial. There were no statistically significant differences in maximal or specific force among treatments. dy(2J) mice treated with 0.1 mg/kg/day omigapil showed decreased percent fibrosis in both gastrocnemius (p<0.03) and diaphragm (p<0.001) compared to vehicle, and in diaphragm (p<0.013) when compared to 1 mg/kg/day omigapil treated mice. Omigapil treated dy(2J) mice demonstrated decreased apoptosis.
  
  
  CONCLUSIONS
  Omigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington DC, United States of America.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Jack
authors.initials: J
authors.lastname: Van der Meulen
authors.forename: Brittany K
authors.initials: BK
authors.lastname: Creeden
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Anne
authors.initials: A
authors.lastname: Rutkowski
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.forename: Kitipong
authors.initials: K
authors.lastname: Uaesoontrachoon
authors.forename: Tony
authors.initials: T
authors.lastname: Huynh
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Spurney
mesh_terms: D000284:Administration, Oral; D000818:Animals; D005355:Fibrosis / Q000517:prevention & control; D005552:Forelimb / Q000187:drug effects* / Q000503:physiopathology; D006614:Hindlimb / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D007797:Laminin / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000503:physiopathology; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D010082:Oxepins / Q000494:pharmacology*; D056152:Respiratory Rate / Q000187:drug effects*
chemical_list: D007797:Laminin; D010082:Oxepins; C111178:dibenzo(b,f)oxepin-10-ylmethyl-methyl-prop-2-ynyl-amine; C102645:laminin alpha 2