Genetic Delivery and Gene Therapy in Pulmonary Hypertension

Abstract

Pulmonary hypertension (PH) is a progressive complex fatal disease of multiple etiologies. Hyperproliferation and resistance to apoptosis of vascular cells of intimal, medial, and adventitial layers of pulmonary vessels trigger excessive pulmonary vascular remodeling and vasoconstriction in the course of pulmonary arterial hypertension (PAH), a subgroup of PH. Multiple gene mutation/s or dysregulated gene expression contribute to the pathogenesis of PAH by endorsing the proliferation and promoting the resistance to apoptosis of pulmonary vascular cells. Given the vital role of these cells in PAH progression, the development of safe and efficient-gene therapeutic approaches that lead to restoration or down-regulation of gene expression, generally involved in the etiology of the disease is the need of the hour. Currently, none of the FDA-approved drugs provides a cure against PH, hence innovative tools may offer a novel treatment paradigm for this progressive and lethal disorder by silencing pathological genes, expressing therapeutic proteins, or through gene-editing applications. Here, we review the effectiveness and limitations of the presently available gene therapy approaches for PH. We provide a brief survey of commonly existing and currently applicable gene transfer methods for pulmonary vascular cells in vitro and describe some more recent developments for gene delivery existing in the field of PH in vivo.

Keywords: gene therapy; pulmonary hypertension; viral gene delivery.

Figure 1

Non-viral and viral delivery systems in pulmonary vascular cells. 7‑NH₂terminus-deleted dominant negative inhibitor of the MCP-1 (7ND MCP‑1); Angiopoietin 1 (Ang‑1); Angiotensin II (Ang II); Bone morphogenetic protein receptor type 2 (BMPR2); Cluster of differentiation 40 (CD‑40); Calcitonin gene-related peptide (CGRP); C‑X‑C chemokine receptor type 4 (CXCR-4); Galectin‑3 (Gal‑3); Fas-induced apoptosis (FIA); Forkhead box O1 (FoxO1); Hypoxia inducible factor‑1α (HIF‑1α); Inhibitor of kappa B mutant (IκBΔN); Intercellular adhesion molecule-1 (ICAM-1); Interleukin 10, (IL‑10); Monocyte chemoattractant protein-1 (MCP‑1); Nitric Oxide (NO); Nuclear factor κB (NF‑κB); Phosphatidylinositol 3-kinase (PI3K); Prolyl hydroxylase domain (PHD); Prostacyclin synthase (PGIS); Ras association domain family 1A (RASSF1A); Sarco‑/endoplasmic reticulum calcium-ATPase 2a (SERCA2a); SMC-specific Rho-associated coiled-coil containing protein kinase 2 (SM22α/ROCK2); Tissue inhibitor matrix metalloproteinase 1 (TIMP‑1); Transgelin (Tagln); Transient receptor potential-1 (Trp1); Tryptophan hydroxylase-1 (Tph1); Tyrosine-protein kinase receptor (Tie2); Twist related protein 1 (Twist); Vascular endothelial growth factor (VEGF); Voltage-gated potassium channel member 5 (Kv1.5); Zinc Finger Protein 580 (ZNF580).