Pulmonary Arterial Hypertension (PAH)

Current pharmacotherapy for pulmonary arterial hypertension (PAH) is aimed at enhancing quality of life and improving hemodynamic parameters, thus improving survival. However, emerging therapies have ambitious goals and are attempting to provide a true cure. They are grouped into 3 main categories: stem cell therapy, gene therapy, and epigenetic medicine. 

Stem Cell Therapy

Endothelial Progenitor Cell Therapy

In 2005, the proof of concept that endothelial progenitor cells (EPCs) can be used to treat PAH was demonstrated in the preclinical setting using murine models. In the study, EPCs demonstrated therapeutic and preventative effects through immune-dependent and paracrine effects.1 A 2019 study has solidified the theory that EPCs have therapeutic potential by demonstrating that stem cell therapy was capable of upregulating bone morphogenetic protein receptor type 2 (BMPR2) signaling pathways in murine models resulting in decreased vascular remodeling and improvement in hemodynamic parameters.2 

Currently, a phase 2 clinical trial titled “Study of Angiogenic Cell Therapy for Progressive Pulmonary Hypertension: Intervention With Repeat Dosing of eNOS-enhanced EPCs” (SAPPHIRE) is recruiting patients. The clinical trial (NCT03001414) seeks to establish the efficacy and safety of repeated monthly dosing of autologous EPCs transfected with human endothelial nitric oxide synthase in patients with symptomatic, severe PAH on available PAH-targeted medical therapy. The estimated completion date is December 2023.3  

Read more about PAH therapies.

Mesenchymal Stem Cell Therapy

Mesenchymal stem cells (MSCs) play an important role in tissue repair and angiogenesis. They appear to migrate to sites of injury and may have regenerative potential in pulmonary vascular disease.4 MSCs have many advantages. They are easy to culture and lack major histocompatibility complex expression, allowing for a favorable immune profile. MSCs appear to exert their regenerative influence through paracrine signaling which involves the transfer of miRNA, mRNA, proteins, cytokines, and lipids via extracellular nanovesicles called exomes.5 MSC-derived exosomes appear to ameliorate pulmonary hypertension in animal models through modulation of lung macrophage phenotype.5 The promising results from these studies are paving the way for future research in human subjects. 

Induced Pluripotent Stem Cell Therapy

Induced pluripotent stem cells (iPSCs) are somatic, adult cells that have undergone reprogramming through transduction of defined transcription factors to an embryonic state. The first study to demonstrate that iPSCs may have utility in treating PAH was conducted in 2016. The study found that iPSC treatment improved hemodynamic parameters, reduced media layer hypertrophy in pulmonary arterioles, and attenuated inflammation in rats with monocrotaline-induced PAH. It is hypothesized that iPSCs reduce production of inflammatory cytokines by inhibiting the phosphorylation of NF-κB – a transcription factor that drives the expression of pro-inflammatory cytokines.6 Whether these findings can be replicated in human patients is yet to be determined.  

Gene Therapy

Bone Morphogenetic Protein Receptor Type 2

Hereditary PAH comprises approximately 6%-10% of PAH cases and more than 450 heterozygous germline mutations to the BMPRII gene have been identified. Restoring BMPR2 signaling through direct delivery of BMPR2 ligands has yielded positive results in murine models carrying a heterozygous mutation to the BMPRII gene. In the study, therapy with a BMPR2 ligand (BMP9) was able to reverse PAH and return right ventricular systolic pressure to the normal range.7 

Another strategy entails delivering the BMPRII gene to pulmonary endothelial cells using an adenovirus-associated vector (AAV). The major limitation of using viral vectors is the inflammatory response generated by the host.8 Gene therapy using AAVs is being investigated in clinical trials. 


Underexpression of sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a) is associated with low intracellular calcium concentrations in pulmonary artery smooth muscle cells and impaired intracellular calcium homeostasis. This is thought to play an important role in pulmonary artery smooth muscle cells by potentiating proliferation, migration, and vascular remodeling through increased activation of STAT3 (signal transducer and activator of transcription-3) and NFATc2 (nuclear factor of activated T-cells) pathways.8  Thus, innovative approaches to restore SERCA2a expression and calcium homeostasis by adenoviral vector-mediated SERCA2a gene transfer represent a new therapeutic strategy in PAH to inhibit the vascular proliferation and remodeling. Results have been positive in animal models.9,10 

Epigenetic Medicine

Epigenetics is defined as a heritable change to the chromatin resulting in a shift in gene expression without altering the DNA sequence.11 

DNA Methyltransferase (DNMT) Inhibitors

Methylation of chromatin represses or silences genes. Hypermethylation of regions of DNA containing the BMPR2 promotor has been documented in patients with hereditary pulmonary hypertension. Therefore, developing targeted treatments that inhibit methylation of specific regions of chromatin could be a novel therapeutic strategy. Currently, this strategy is mostly theoretical and requires more investigation.8 

Histone Deacetylase (HDAC) Inhibitors

Histone acetylation favors the unwinding of chromatin to a less compact form and allows for genes to become more accessible for transcription.12 Histone deacetylase (HDAC) removes acetyl groups from histones, increasing chromatin compacting and inhibiting transcription of involved genes. Two studies in animal models have demonstrated that inhibition of histone deacetylases improves PAH by reducing right ventricular remodeling and improving cardiac function.8 HDAC inhibitors are currently FDA-approved for treating other conditions such as cancer but their utility in treating PAH has not yet been established in humans. 

Bromodomain and Extra-Terminal (BET) Motif Inhibitors

While HDAC is responsible for removing acetyl groups from histones, the bromodomain and extra-terminal (BET) proteins are responsible for reading histone acetylation marks. One BET protein called BRD4 is under investigation as a potential anti-cancer agent. BET proteins act as transcription factors by interacting with the transcription elongation factor complex and regulate transcriptional elongation by RNA polymerase II through phosphate-dependent mechanism.8 

High BRD4 levels have been described in biopsy specimens of pulmonary arteries from patients with PAH, which prompted further investigation as to whether BET motif inhibitors have potential therapeutic benefit. In 2015 it was demonstrated that inhibition of BRD4 stabilizes the balance between proliferation and apoptosis of pulmonary artery smooth muscle cells.13 Later, a preclinical trial revealed that inhibition of BRD4 resulted in a reversal of PAH phenotype in isolated PAH microvascular endothelial cells and smooth muscle cells in vitro, and in diverse PAH rat models and improved right ventricular pressure load.14 

The results from the latter study established the basis for an ongoing clinical trial using apabetalone, a BRD4 inhibitor. The trial (NCT03655704) is currently recruiting participants.15


1. Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005;96(4):442-450. doi:10.1161/01.RES.0000157672.70560.7b

2. Harper RL, Maiolo S, Ward RJ, et al. BMPR2-expressing bone marrow-derived endothelial-like progenitor cells alleviate pulmonary arterial hypertension in vivo. Respirol Carlton Vic. 2019;24(11):1095-1103. doi:10.1111/resp.13552

3. A multicentre, late phase clinical trial to establish the efficacy and safety of repeat dosing of autologous endothelial progenitor cells (EPCs) transfected with human endothelial NO-synthase (ENOS) in patients with pulmonary arterial hypertension (PAH) on top of conventional treatments. ClinicalTrials.gov. Accessed July 1, 2021.

4. Suen CM, Mei SHJ, Kugathasan L, Stewart DJ. Targeted delivery of genes to endothelial cells and cell- and gene-based therapy in pulmonary vascular diseases. Compr Physiol. 2013;3(4):1749-1779. doi:10.1002/cphy.c120034

5. Nikfarjam S, Rezaie J, Zolbanin NM, Jafari R. Mesenchymal stem cell derived-exosomes: a modern approach in translational medicine. J Transl Med. 2020;18(1):449. doi:10.1186/s12967-020-02622-3

6. Huang W-C, Ke M-W, Cheng C-C, et al. Therapeutic benefits of induced pluripotent stem cells in monocrotaline-induced pulmonary arterial hypertension. PloS One. 2016;11(2):e0142476. doi:10.1371/journal.pone.0142476

7. Long L, Ormiston ML, Yang X, et al. Selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension. Nat Med. 2015;21(7):777-785. doi:10.1038/nm.3877

8. Bisserier M, Pradhan N, Hadri L. Current and emerging therapeutic approaches to pulmonary hypertension. Rev Cardiovasc Med. 2020;21(2):163-179. doi:10.31083/j.rcm.2020.02.597

9. Strauss B, Sassi Y, Bueno-Beti C, et al. Intra-tracheal gene delivery of aerosolized SERCA2a to the lung suppresses ventricular arrhythmias in a model of pulmonary arterial hypertension. J Mol Cell Cardiol. 2019;127:20-30. doi:10.1016/j.yjmcc.2018.11.017

10. Watanabe S, Ishikawa K, Plataki M, et al. Safety and long-term efficacy of AAV1.SERCA2a using nebulizer delivery in a pig model of pulmonary hypertension. Pulm Circ. 2018;8(4):2045894018799738. doi:10.1177/2045894018799738

11. Weinhold B. Epigenetics: the science of change. Environ Health Perspect. 2006;114(3):A160-167. doi:10.1289/ehp.114-a160

12. Eberharter A, Becker PB. Histone acetylation: a switch between repressive and permissive chromatin. EMBO Rep. 2002;3(3):224-229. doi:10.1093/embo-reports/kvf053

13. Meloche J, Potus F, Vaillancourt M, et al. Bromodomain-containing protein 4: the epigenetic origin of pulmonary arterial hypertension. Circ Res. 2015;117(6):525-535. doi:10.1161/CIRCRESAHA.115.307004

14. Van der Feen DE, Kurakula K, Tremblay E, et al. Multicenter preclinical validation of BET inhibition for the treatment of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2019;200(7):910-920. doi:10.1164/rccm.201812-2275OC

15. Apabetalone for pulmonary arterial hypertension: a pilot study. ClinicalTrials.gov. Accessed July 1, 2021.

Reviewed by Harshi Dhingra, MD, on 7/1/2021.