title: Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension: A Large Animal Model.
abstract: Pulmonary hypertension (PH) is characterized by pulmonary arterial remodeling that results in increased pulmonary vascular resistance, right ventricular (RV) failure, and premature death. Down-regulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca(2+)) homeostasis and transition of pulmonary artery smooth muscle cells to a proliferative phenotype.
  
  
  
  We assessed the feasibility of sustained pulmonary vascular SERCA2a gene expression using aerosolized delivery of adeno-associated virus type 1 (AAV1) in a large animal model of chronic PH and evaluated the efficacy of gene transfer regarding progression of pulmonary vascular and RV remodeling.
  
  
  
  A model of chronic post-capillary PH was created in Yorkshire swine by partial pulmonary vein banding. Development of chronic PH was confirmed hemodynamically, and animals were randomized to intratracheal administration of aerosolized AAV1 carrying the human SERCA2a gene (n = 10, AAV1.SERCA2a group) or saline (n = 10). Therapeutic efficacy was evaluated 2 months after gene delivery.
  
  
  
  Transduction efficacy after intratracheal delivery of AAV1 was confirmed by β-galactosidase detection in the distal pulmonary vasculature. Treatment with aerosolized AAV1.SERCA2a prevented disease progression as evaluated by mean pulmonary artery pressure, vascular resistance, and limited vascular remodeling quantified by histology. Therapeutic efficacy was supported further by the preservation of RV ejection fraction (p = 0.014) and improvement of the RV end-diastolic pressure-volume relationship in PH pigs treated with aerosolized AAV1.SERCA2a.
  
  
  
  Airway-based delivery of AAV vectors to the pulmonary arteries was feasible, efficient, and safe in a clinically relevant chronic PH model. Vascular SERCA2a overexpression resulted in beneficial effects on pulmonary arterial remodeling, with attendant improvements in pulmonary hemodynamics and RV performance, and might offer therapeutic benefit by modifying fundamental pathophysiology in pulmonary vascular diseases.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Aguero
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.affiliation: Atherothrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Carlos G
authors.initials: CG
authors.lastname: Santos-Gallego
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Fish
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Erik
authors.initials: E
authors.lastname: Kohlbrenner
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Nadjib
authors.initials: N
authors.lastname: Hammoudi
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Changwon
authors.initials: C
authors.lastname: Kho
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Ahyoung
authors.initials: A
authors.lastname: Lee
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; IIS Fundacion Jimenez-Diaz Hospital, Madrid, Spain.
authors.forename: Borja
authors.initials: B
authors.lastname: Ibáñez
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: García-Alvarez
authors.affiliation: Biovest Consulting, LLC, Santa Barbara, California.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Zsebo
authors.affiliation: Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Bradley A
authors.initials: BA
authors.lastname: Maron
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Maria
authors.initials: M
authors.lastname: Plataki
authors.affiliation: Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York.
authors.forename: Valentin
authors.initials: V
authors.lastname: Fuster
authors.affiliation: Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: roger.hajjar@mssm.edu.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000336:Aerosols; D000818:Animals; D000229:Dependovirus; D004195:Disease Models, Animal; D005240:Feasibility Studies; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006976:Hypertension, Pulmonary / Q000628:therapy*; D008168:Lung / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics* / Q000494:pharmacology; D013318:Stroke Volume; D013552:Swine; D066253:Vascular Remodeling; D020257:Ventricular Remodeling; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000336:Aerosols; D001616:beta-Galactosidase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: aerosol delivery; gene therapy; pig models; pulmonary vascular remodeling; right ventricular function