Leveraging Pulmonary Arterial Hypertension Patient Cells for Drug Discovery
by Amanda Chase, PhD
July 19, 2021
Pulmonary arterial hypertension (PAH) occurs when the arteries in the lung become narrowed and/or blocked. It is a rare, progressive form of high blood pressure that affects lungs. Progressive means that over time, as the heart continues to work harder to circulate blood in the lungs, the heart muscle can weaken and fail. PAH is considered rare in that there are 500-1000 new cases per year in the US, with most of them being women between 30-60 years of age. While the exact cause of PAH is unknown, it is believed that PAH occurs when there is some injury or dysfunction in the endothelial and smooth muscle cells that line the blood vessels of the lung, that in turn results in the narrowing and blockage of the arteries. Current treatments for PAH are aimed at managing the condition: improving symptoms and slowing progression. However, there is no cure for PAH, and thus an unmet medical need to develop such a therapy as well as to identify agents that may cause PAH.
Previously, animal models have been used to identify potential therapies. Unfortunately, due to considerable species differences, a majority (90%) of drugs that perform well in animal models fail in clinical trials. To address the need, researchers led by Cardiovascular Institute affiliated first author Mingxia Gu, currently an Assistant Professor at the Cincinnati Children’s Hospital Medical Center, and senior author Marlene Rabinovitch, together with Purvesh Khatri and his team in Biomedical Data Science utilized relatively new tools to identify promising PAH therapies. Their findings, recently published in Science Translational Medicine, share not only a potential candidate for curing PAH, but also describe a workflow to accelerate drug discovery for specific diseases, such as PAH.
Induced pluripotent stem cell (iPSC) technology enables the use of tissue-specific human cells that have the same genetic background as patients. In this study, iPSCs from PAH patients were programmed into endothelial cells (iPSC-ECs), providing a platform to first determine the effects of different drugs on improving survival and potential for regeneration after injury (drug screening). Researchers were able to screen a library of 4500 different compounds at different stages of clinical development, looking for any that improved survival of the iPSC-ECs from PAH patients. Intriguingly, they were able to identify a compound, tyrphostin or AG1296, as having the greatest potential as a therapy.
With follow-up tests and analyses, they showed that AG1296 performed exceptionally well at improving PAH vascular function, and the researchers were able to provide an explanation for why AG1296 was able to improve PAH cell function. This critical finding will need to next be tested in a clinical trial to determine whether AG1296 is indeed a new treatment for clinical PAH. This study has additional significance in that it describes a means to accelerate drug discovery for PAH treatment, by combining the use of patient-specific iPSC cells for functional screening In combination with analysis of available drug and PAH datasets. This combined approach enables rapid identification of a promising lead compound and also identifies its mechanism of action. This strategy can also be used to identify other therapies that may be particularly beneficial to a specific group of PAH patients, and other drugs that worsen the function of the blood vessel cells and should be avoided.
Other Stanford Cardiovascular Institute affiliated authors include Yifei Miao, Shuai Mao, Toshie Siaito, Shoichiro Otsuki, Lingli Wang, Rebecca Harper, and Silin Sa. Other authors included Michele Donato and Purvesh Khatri from Stanford University School of Medicine, and Minzhe Guo and Neil Wary (currently at Stanford University) from University of Cincinnati College of Medicine.