In PAH, Resistin Could Be Key Biomarker and Therapeutic Target

New research into the associations between the cytokine resistin and pulmonary arterial hypertension (PAH) has yielded a new biomarker of disease severity and potentially a new therapeutic option.

PAH is a life-altering—and life-threatening—condition. Yet, until relatively recently the therapeutic options have been limited. The approval of sotatercept (Winrevair) earlier this year marked a significant step forward, with one population health model suggesting the therapy could extend the lives of patients by an average of more than 11 years when added to background therapy.

Still, the quest to better understand and reverse the disease continues. One of the most promising avenues in that effort is centered on the role of resistin.

Resistin was first identified more than two decades ago when investigators noticed that circulating levels of the cytokine were decreased by an anti-diabetic drug and were increased in patients with obesity. They dubbed these cytokines “resistin” for their resistance to insulin. Since then, further research has shown that resistin is also linked with outcomes in patients with cardiovascular disease and heart failure.

Resistin is part of the resistin-like molecule (RELM) family of pleiotropic cytokines, which Roger A. Johns , M.D., M.H.S., Ph.D., of Johns Hopkins University, and colleagues, have demonstrated is involved in the type 2 inflammatory response to tissue injuries in the lungs and other organs.

Moreover, they showed that in rodent models, a mouse homolog of resistin led to vascular remodeling and hemodynamic changes similar to those that occur in PAH. That evidence, in addition to other research, led Johns and colleagues to a hypothesis: perhaps serum resistin levels could serve as a mechanistic biomarker of severity and survival in patients with PAH.

Johns and colleagues recently published their investigation into that question in a report in Respiratory Research. They turned to the National Institutes of Health’s National Biological Sample and Data Repository for PAH, from which they received clinical data and biological samples from 1,121 patients with PAH, including 808 with idiopathic PAH and 313 with scleroderma-associated PAH. They also obtained samples from 50 healthy participants to act as controls. The investigators then measured serum resistin levels for the samples, and compared those to clinical variables and outcomes. Lastly, they used machine learning algorithms to develop risk models for mortality prediction.

Johns and colleagues found that serum resistin levels were uniformly higher in patients with PAH compared to healthy controls. Moreover, they found that older age, shorter six-minute walking distance (6MWD), reduced cardiac performance, and risk of death were all associated with higher levels of resistin.

In addition, the investigators’ machine learning analysis of resistin as a predictor of mortality showed that including resistin levels in survival models improved their accuracy.

“In our paper, we did statistical testing to see if resistin helped the predictive ability of the different combinations of existing biomarkers,” Johns said, “and it did.”

However, Johns sees the findings as more than just a pathway to a new biomarker. He believes it could also be the key to new therapies. The theory is that, if increased PAH is associated with disease severity, perhaps therapeutically decreasing resistin can lead to improvement or prevention of the disease. Johns said the evidence from rodent models is strong.

“It [resistin] is extremely effective in preventing or reducing induction of PAH in rodent models (chronic hypoxia, sugen hypoxia, monocrotaline),” he said. “...We expect that it will markedly reduce the severity of the disease with reduction in mortality and associated improved quality of life.”

Johns and colleagues are now working on a therapy based on their resistin findings, with the hope of soon filing an investigational new drug (IND) application with the Food and Drug Administration (FDA).

“We have developed a human therapeutic antibody against resistin for PAH that we are preparing for FDA IND, and hopefully clinical trials,” he said.