title: Percutaneous cardiac recirculation-mediated gene transfer of an inhibitory phospholamban peptide reverses advanced heart failure in large animals.
abstract: OBJECTIVE
  The purpose of this study was to develop a clinically applicable high-efficiency percutaneous means of therapeutic gene delivery to the failing heart.
  
  
  BACKGROUND
  Substantial advances in the understanding of the cellular and molecular basis of heart failure (HF) have recently fostered interest in the potential utility of gene and cell therapy as novel therapeutic approaches. However, successful clinical translation is currently limited by the lack of safe, efficient, and selective delivery systems.
  
  
  METHODS
  We developed a novel percutaneous closed-loop recirculatory system that provides homogeneous myocardial delivery for gene transfer in the failing large animal heart. After 4 weeks' rapid pacing in adult sheep to induce HF, the animals were randomly allocated to receive either adenovirus expressing a pseudophosphorylated mutant (AdS16E) of phospholamban (PLN) or Ad-beta-galactosidase (AdLacZ).
  
  
  RESULTS
  Two weeks after gene delivery, in the presence of continued pacing, left ventricular (LV) ejection fraction had significantly improved in the AdS16E-treated animals (27 +/- 3% to 50 +/- 4%; p < 0.001), whereas a further decline occurred in the AdLacZ group (34 +/- 4% to 27 +/- 3%; p < 0.05). In conjunction, AdS16E delivery resulted in significant reductions in LV filling pressures and end-diastolic diameter (both p < 0.05). In conjunction, AdS16E-treated animals showed significant improvement in the expression of PLN and Ca2+-adenosine triphosphatase activity. In separate animals, recirculating AdLacZ delivery was shown to achieve superior myocardial gene expression in contrast to intracoronary delivery and was associated with lower systemic expression.
  
  
  CONCLUSIONS
  We report the development of a novel closed-loop system for cardiac gene therapy. Using this approach delivery of AdS16E reversed HF progression in a large animal HF model.
authors.affiliation: Baker Heart Research Institute, Melbourne, Australia. david.kaye@baker.edu.au
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
authors.forename: Arthur
authors.initials: A
authors.lastname: Preovolos
authors.forename: Tanneale
authors.initials: T
authors.lastname: Marshall
authors.forename: Melissa
authors.initials: M
authors.lastname: Byrne
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hoshijima
authors.forename: Roger
authors.initials: R
authors.lastname: Hajjar
authors.forename: Justin A
authors.initials: JA
authors.lastname: Mariani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Pepe
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: John M
authors.initials: JM
authors.lastname: Power
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000494:pharmacology*; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006333:Heart Failure / Q000503:physiopathology / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D011336:Probability; D011897:Random Allocation; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012756:Sheep; D018709:Statistics, Nonparametric; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D000099211:Phospholamban