Edda Spiekerkoetter

Research in pulmonary arterial hypertension has reached a turning point in several areas. Should research continue its quest to find novel PAH genes? Should it continue to employ animal models? These topics and more will be debated Tuesday morning to help clarify the alternatives and chart future research.

“We want to engage basic scientists and physician-scientists in pulmonary arterial hypertension to debate what they think about the pathogenesis of this disease and ways forward to find treatments that work in patients, not just in animal models,” said Edda Spiekerkoetter, MD. “We want to encourage research in more fruitful directions. And by focusing on hot topics in PAH research, the debates will offer junior scientists an excellent overview of current schools of thought of PAH pathogenesis.”

Dr. Spiekerkoetter will co-chair the debate. She is associate professor of pulmonary and critical care medicine at Stanford University Medical Center in California, co-director of the Hereditary Hemorrhagic Telangiectasias (HHT) Center, and director of HHT research at Stanford University. She will share the stage with Soni S. Pullamsetti, PhD, principal investigator at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, and Wolfgang Kuebler, MD, professor at Charité-Universitätsmedizin in Berlin, Germany.

The debaters will tackle opposing views on four of key areas in pulmonary vascular disease.

The first question focuses on the role of the right ventricle in PAH. Most PAH patients die of right heart disease, Dr. Spiekerkoetter said. It is not clear, though, whether the research should focus on the mechanisms of right ventricle failure and approaches to improve its performance or if focusing on the overall improvement of existing pulmonary vascular disease is more likely to be productive.

The second debate homes in on the utility of novel PAH disease genes. Continuing improvements in genetic research techniques are revealing more genes associated with PAH, but it is not at all clear how useful these novel genes might be.

“Pulmonary hypertension is already a rare disease, so will finding genetic variants that are even more rare really help us?”
Dr. Spiekerkoetter asked. “One point of view is that these new genes do not affect so many people. But as we have seen in other diseases, rare genetic variants might guide us to recognize new pathways that help us to create new treatments. There is no clear or simple answer to these questions.”

The third debate examines the utility of animal models. The first rodent models of PAH were a breakthrough, but no new clinical treatments have been developed as a result.

“It was a great thing 20 years ago to say we have reversed existing pulmonary hypertension in a mouse,” Dr. Spiekerkoetter said. “Now we have many papers like this every year, but so far none of these approaches has been shown to be beneficial in patients. Do we continue on with animal models or do we focus more on human tissue models to find drugs that are effective in patients? Or, because we know the immune system is involved in pulmonary hypertension, do we use mice with a humanized immune system to study PH? This all comes down to finding ways we can do better.”

The final debate evaluates the role of precision medicine. Tailoring treatment to the individual patient is the hottest frontier in medical research. Should PAH research follow the crowd?

“Precision medicine is difficult to test in a rare disease,” Dr. Spiekerkoetter noted. “It is easy to create many subgroups in PAH, yet we might never be able to perform a clinical trial on subgroups of PAH that is powered to show significant changes. A different approach would be to say that despite different etiologies, the phenotype of pulmonary hypertension is pretty much the same; therefore, we should be looking for common pathways to treat. We want to encourage thinking and discussion of these issues.”

Educational Grant Support: Actelion Pharmaceuticals US, Inc. and Bayer US.