Author + information
- Received January 26, 2016
- Revision received February 16, 2016
- Accepted February 17, 2016
- Published online May 3, 2016.
- Jaume Aguero, MDa,b,
- Kiyotake Ishikawa, MDa,
- Lahouaria Hadri, PhDa,
- Carlos G. Santos-Gallego, MDc,
- Kenneth M. Fish, PhDa,
- Erik Kohlbrenner, BSa,
- Nadjib Hammoudi, MD, PhDa,
- Changwon Kho, PhDa,
- Ahyoung Lee, PhDa,
- Borja Ibáñez, MD, PhDb,d,
- Ana García-Alvarez, MD, PhDb,
- Krisztina Zsebo, PhDe,
- Bradley A. Maron, MDf,
- Maria Plataki, MDa,
- Valentin Fuster, MD, PhDb,g,
- Jane A. Leopold, MDf and
- Roger J. Hajjar, MDa,∗ ()
- aCardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, New York
- bCentro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain
- cAtherothrombosis Research Unit, Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York
- dIIS Fundacion Jimenez-Diaz Hospital, Madrid, Spain
- eBiovest Consulting, LLC, Santa Barbara, California
- fCardiovascular Medicine Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
- gZena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York
- ↵∗Reprint requests and correspondence:
Dr. Roger J. Hajjar, Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, #1030, New York, New York 10029.
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 Ca2+-ATPase 2a (SERCA2a) in the pulmonary vasculature leads to perturbations in calcium ion (Ca2+) 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.
This work is supported by National Institutes of Health grants RO1 HL083156, HL093183, HL119046, and P20HL100396 and a National Heart, Lung, and Blood Institute Program of Excellence in Nanotechnology Award; contract HHSN268201000045C (to Dr. Hajjar); and National Institutes of Health R01105301 and U01 125215 (to Dr. Leopold). Part of the work was funded by a Leducq Foundation grant (to Dr. Hajjar). Dr. Aguero was supported by the Fundacion Alfonso Martin-Escudero. Dr. Hammoudi was supported by the French Federation of Cardiology; and has received a research grant from Laboratoires Servier. Dr. Maron is the recipient of an investigator-initiated grant from Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Leopold and Hajjar contributed equally to this work. David A. Dicheck, MD, served as Guest Editor for this paper.
- Received January 26, 2016.
- Revision received February 16, 2016.
- Accepted February 17, 2016.
- American College of Cardiology Foundation