Jaume Aguero1, Kiyotake Ishikawa2, Lahouaria Hadri2, Carlos G Santos-Gallego3, Kenneth M Fish2, Erik Kohlbrenner2, Nadjib Hammoudi2, Changwon Kho2, Ahyoung Lee2, Borja Ibáñez4, Ana García-Alvarez5, Krisztina Zsebo6, Bradley A Maron7, Maria Plataki2, Valentin Fuster8, Jane A Leopold7, Roger J Hajjar9. 1. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York; Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. 2. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York. 3. Atherothrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 4. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; IIS Fundacion Jimenez-Diaz Hospital, Madrid, Spain. 5. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain. 6. Biovest Consulting, LLC, Santa Barbara, California. 7. Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 8. 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. 9. Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York. Electronic address: roger.hajjar@mssm.edu.
Abstract
BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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: Lahouaria Hadri; Razmig G Kratlian; Ludovic Benard; Bradley A Maron; Peter Dorfmüller; Dennis Ladage; Christophe Guignabert; Kiyotake Ishikawa; Jaume Aguero; Borja Ibanez; Irene C Turnbull; Erik Kohlbrenner; Lifan Liang; Krisztina Zsebo; Marc Humbert; Jean-Sébastien Hulot; Yoshiaki Kawase; Roger J Hajjar; Jane A Leopold Journal: Circulation Date: 2013-06-26 Impact factor: 29.690
Authors: Kiyotake Ishikawa; Kenneth M Fish; Lisa Tilemann; Kleopatra Rapti; Jaume Aguero; Carlos G Santos-Gallego; Ahyoung Lee; Ioannis Karakikes; Chaoqin Xie; Fadi G Akar; Yuichi J Shimada; Judith K Gwathmey; Aravind Asokan; Scott McPhee; Jade Samulski; Richard Jude Samulski; Daniel C Sigg; Thomas Weber; Evangelia G Kranias; Roger J Hajjar Journal: Mol Ther Date: 2014-07-15 Impact factor: 11.454
Authors: M Sean McMurtry; Rohit Moudgil; Kyoko Hashimoto; Sandra Bonnet; Evangelos D Michelakis; Stephen L Archer Journal: Am J Physiol Lung Cell Mol Physiol Date: 2006-12-01 Impact factor: 5.464
Authors: Mariëlle C van de Veerdonk; Taco Kind; J Tim Marcus; Gert-Jan Mauritz; Martijn W Heymans; Harm-Jan Bogaard; Anco Boonstra; Koen M J Marques; Nico Westerhof; Anton Vonk-Noordegraaf Journal: J Am Coll Cardiol Date: 2011-12-06 Impact factor: 24.094
Authors: Christian Gerges; Mario Gerges; Marie B Lang; Yuhui Zhang; Johannes Jakowitsch; Peter Probst; Gerald Maurer; Irene M Lang Journal: Chest Date: 2013-03 Impact factor: 9.410
Authors: Nazzareno Galiè; Marius M Hoeper; Marc Humbert; Adam Torbicki; Jean-Luc Vachiery; Joan Albert Barbera; Maurice Beghetti; Paul Corris; Sean Gaine; J Simon Gibbs; Miguel Angel Gomez-Sanchez; Guillaume Jondeau; Walter Klepetko; Christian Opitz; Andrew Peacock; Lewis Rubin; Michael Zellweger; Gerald Simonneau Journal: Eur Heart J Date: 2009-08-27 Impact factor: 29.983
Authors: Krisztina Zsebo; Alex Yaroshinsky; Jeffrey J Rudy; Kim Wagner; Barry Greenberg; Mariell Jessup; Roger J Hajjar Journal: Circ Res Date: 2013-09-24 Impact factor: 17.367
Authors: D Gaudet; J Méthot; S Déry; D Brisson; C Essiembre; G Tremblay; K Tremblay; J de Wal; J Twisk; N van den Bulk; V Sier-Ferreira; S van Deventer Journal: Gene Ther Date: 2012-06-21 Impact factor: 5.250
Authors: Benjamin Strauss; Yassine Sassi; Carlos Bueno-Beti; Zeki Ilkan; Nour Raad; Marine Cacheux; Malik Bisserier; Irene C Turnbull; Erik Kohlbrenner; Roger J Hajjar; Lahouaria Hadri; Fadi G Akar Journal: J Mol Cell Cardiol Date: 2018-11-28 Impact factor: 5.000
Authors: Malik Bisserier; Javier Milara; Yassine Abdeldjebbar; Sarah Gubara; Carly Jones; Carlos Bueno-Beti; Elena Chepurko; Erik Kohlbrenner; Michael G Katz; Sima Tarzami; Julio Cortijo; Jane Leopold; Roger J Hajjar; Yassine Sassi; Lahouaria Hadri Journal: Mol Ther Date: 2019-12-06 Impact factor: 11.454
Authors: Evan L Brittain; Thennapan Thennapan; Bradley A Maron; Stephen Y Chan; Eric D Austin; Edda Spiekerkoetter; Harm J Bogaard; Christophe Guignabert; Roxane Paulin; Roberto F Machado; Paul B Yu Journal: Am J Respir Crit Care Med Date: 2018-07-01 Impact factor: 21.405
Authors: Jane A Leopold; Steven M Kawut; Micheala A Aldred; Stephen L Archer; Ray L Benza; Michael R Bristow; Evan L Brittain; Naomi Chesler; Frances S DeMan; Serpil C Erzurum; Mark T Gladwin; Paul M Hassoun; Anna R Hemnes; Tim Lahm; Joao A C Lima; Joseph Loscalzo; Bradley A Maron; Laura Mercer Rosa; John H Newman; Susan Redline; Stuart Rich; Franz Rischard; Lissa Sugeng; W H Wilson Tang; Ryan J Tedford; Emily J Tsai; Corey E Ventetuolo; YouYang Zhou; Neil R Aggarwal; Lei Xiao Journal: Circ Heart Fail Date: 2021-06-15 Impact factor: 10.447