Michael G. Katz, Yoav Hadas, Adam Vincek, Lina Freage‑Kahn, Nataly Shtraizent, Jeko M. Madjarov, Peter Pastuszko, Efrat Eliyahu
Icahn School of Medicine at Mount Sinai. SeneX Therapeutics Inc. Atrium Health Sanger Heart and Vascular Institute. Wake Forest School of Medicine.
United States
Respiratory Research
Respir Res 2023; 24
DOI: 10.1186/s12931-023-02487-2
Abstract
Background: Up-regulation of ceramides in pulmonary hypertension (PH), contributing to perturbations in sphingolipid homeostasis and the transition of cells to a senescence state. We assessed the safety, feasibility, and efficiency of acid ceramidase gene transfer in a rodent PH model.
Methods: A model of PH was established by the combination of left pneumonectomy and injection of Sugen toxin. Magnetic resonance imaging and right heart catheterization confirmed development of PH. Animals were subjected to intratracheal administration of synthetic adeno-associated viral vector (Anc80L65) carrying the acid ceramidase (Anc80L65.AC), an empty capsid vector, or saline. Therapeutic efficacy was evaluated 8 weeks after gene delivery.
Results: Hemodynamic assessment 4 weeks after PH model the development demonstrated an increase in the mean pulmonary artery pressure to 30.4 ± 2.13 mmHg versus 10.4 ± 1.65 mmHg in sham (p < 0.001), which was consistent with the definition of PH. We documented a significant increase in pulmonary vascular resistance in the saline-treated (6.79 ± 0.85 mm Hg) and empty capsid (6.94 ± 0.47 mm Hg) groups, but not in animals receiving Anc80L65.AC (4.44 ± 0.71 mm Hg, p < 0.001). Morphometric analysis demonstrated an increase in medial wall thickness in control groups in comparison to those treated with acid ceramidase. After acid ceramidase gene delivery, a significant decrease of pro-inflammatory factors, interleukins, and senescence markers was observed.
Conclusion: Gene delivery of acid ceramidase provided tropism to pulmonary tissue and ameliorated vascular remodeling with right ventricular dysfunction in pulmonary hypertension.
Category
Animal Models of Pulmonary Vascular Disease and Therapy
Class I. Pulmonary Hypertension Associated with Inflammation
Genetic Factors Associated with Pulmonary Vascular Disease
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Filed (PHiled). Greater than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes