title: In vivo cardiac myosin binding protein C gene transfer rescues myofilament contractile dysfunction in cardiac myosin binding protein C null mice.
abstract: BACKGROUND
  Decreased expression of cardiac myosin binding protein C (cMyBPC) in the heart has been implicated as a consequence of mutations in cMyBPC that lead to abnormal contractile function at the myofilament level, thereby contributing to the development of hypertrophic cardiomyopathy in humans. It has not been established whether increasing the levels of cMyBPC in the intact heart can improve myofilament and in vivo contractile function and attenuate maladaptive remodeling processes because of reduced levels of cMyBPC.
  
  
  RESULTS
  We performed in vivo gene transfer of cMyBPC by direct injection into the myocardium of cMyBPC-deficient (cMyBPC(-/-)) mice, and mechanical experiments were conducted on skinned myocardium isolated from cMyBPC(-/-) hearts 21 days and 20 weeks after gene transfer. Cross-bridge kinetics in skinned myocardium isolated from cMyBPC(-/-) hearts after cMyBPC gene transfer were significantly slower compared with untreated cMyBPC(-/-) myocardium and were comparable to wild-type myocardium and cMyBPC(-/-) myocardium that was reconstituted with recombinant cMyBPC in vitro. cMyBPC content in cMyBPC(-/-) skinned myocardium after in vivo cMyBPC gene transfer or in vitro cMyBPC reconstitution was similar to wild-type levels. In vivo echocardiography studies of cMyBPC(-/-) hearts after cMyBPC gene transfer revealed improved systolic and diastolic contractile function and reductions in left ventricular wall thickness.
  
  
  CONCLUSIONS
  This proof-of-concept study demonstrates that gene therapy designed to increase expression of cMyBPC in the cMyBPC-deficient myocardium can improve myofilament and in vivo contractile function, suggesting that cMyBPC gene therapy may be a viable approach for treatment of cardiomyopathies because of mutations in cMyBPC.
authors.affiliation: Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Merkulov
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Chen
authors.forename: Margaret P
authors.initials: MP
authors.lastname: Chandler
authors.forename: Julian E
authors.initials: JE
authors.lastname: Stelzer
mesh_terms: D000818:Animals; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005240:Feasibility Studies; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D007700:Kinetics; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000378:metabolism; D020127:Recovery of Function; D014463:Ultrasonography; D016277:Ventricular Function, Left; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D011994:Recombinant Proteins; D000099163:Myosin Binding Protein C