Cell Therapies Show Potential as Treatment for PAH, Review Finds

Regenerative cell therapy can induce significant improvements in key clinical features of pulmonary arterial hypertension (PAH) in animal models, a review study shows.

The study’s findings suggest that such treatment may represent a suitable approach to treat PAH in humans. Still, further testing is necessary to demonstrate the safety and efficacy of regenerative cell therapy.

The review study findings were discussed in an article, titled “Regenerative cell therapy for pulmonary arterial hypertension in animal models: a systematic review,” published in the journal Stem Cell Research & Therapy.

Several preclinical and clinical studies have explored the potential of using specific types of cells to restore the normal metabolic balance in the lungs, and reverse the structural changes associated with PAH.

To date, the most commonly tested cells were early-outgrowth endothelial progenitor cells, or EPCs, and mesenchymal stromal cells, or MSCs. They have demonstrated the ability to migrate to sites where blood vessels are damaged, and secrete signaling factors that can induce vascular repair and reduce inflammation.

Preclinical studies have also shown that EPCs and MSCs can reduce pulmonary pressure and tissue remodeling, while helping regenerate injured blood vessels.

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Furthermore, data from three small clinical trials (NCT00257413, NCT00641836, and NCT00469027) have provided relatively modest evidence that cell therapies can limit PAH burden in humans.

Canadian researchers have now reviewed and compared data from 45 studies on the impact of different regenerative cell therapies in PAH animal models.

“A synthesis of this preclinical data may identify knowledge gaps, impact the design of further preclinical testing of cell therapies, and potentially influence the design of future clinical trials,” researchers said.

The majority of the studies were conducted in rats with PAH, with two studies using dogs to test the cell therapies. The cell types used in these studies included bone marrow mononuclear cells (BM-MNC), cardiosphere-derived cells (CDC), EPCs, induced pluripotent stem cells (iPSC), and MSCs.

More than half of the studies, including data from approximately 805 animals, showed that cell therapy was associated with a significant reduction in right ventricular systolic pressure (RVSP) — a commonly used clinical marker of PAH. In particular, treatments that used enhanced cells, either by genetic manipulation or by small molecule pretreatment, were linked to greater reduction in RVSP compared to non-enhanced cells.

Among the cell types used in these studies, all except BM-MNC effectively reduced RVSP in PAH animal models. MSCs had a significantly greater effect in lowering RVSP compared to EPCs.

Analysis of cell therapies’ impact on mean pulmonary arterial pressure (mPAP) — another important clinical outcome in PAH patients — showed a significant beneficial effect, meaning a significant reduction in mPAP compared to controls.

The team found that enhanced and non-enhanced cells had similar effects on mPAP, although there was limited data from enhanced cell studies. In addition, both EPCs and MSCs induced significant reduction in mPAP in PAH animal models, with no significant benefit of one cell type over the other.

No differences on RVSP and mPAP outcomes were found when using cells that came from a donor (allogeneic), from the animal itself (autologous), or if they were human cells (xenogeneic).

Regenerative cell therapy was also found to be associated with an overall decrease in the heart’s right ventricle remodeling. Still, this treatment strategy had no significant impact on preventing the death of the animals.

According to the team, although this review study showed that regenerative cell therapy can have a positive effect on major clinical features of PAH in animal models, it also revealed that many of the studies failed to effectively control for inherent bias.

“Inadequate generation or concealment of allocation is associated with exaggerated effect sizes,” researchers wrote. Allocation concealment refers to a technique used to prevent selection bias in randomized studies, by concealing the allocation sequence from those assigning participants (or animals) to the intervention or control groups.

The team therefore suggested that additional studies are warranted to further validate these preclinical results, and that such studies should include more comprehensive assessments of cardiac function, such as right ventricle functional capacity.

“Preclinical studies of regenerative cell therapy demonstrated efficacy in animal models of PAH; however, future studies should consider incorporating design elements to reduce the risk of bias,” the researchers said, adding that “at this time, limited data and lack of head-to-head comparisons preclude the suggestion of an optimal method of cell therapy [for PAH].”