NEW YORK (Reuters Health) – High-throughput screening combined with in silico bioinformatics analyses identified a compound that reversed blood vessel damage and halted lesion formation in a rat model of pulmonary arterial hypertension (PAH), and in lung cultures, researchers say.
PAH is a progressive, potentially fatal disease in which blood vessels in the lung become occluded, fluoxetine toxic dose and for which there is no known cure.
“To address this unmet need, we interrogated readily available patient-specific induced pluripotent stem cell (iPSC)-derived vascular cells for a favorable disease-modifying response and chose among our top ‘hits’ the lead compound with the most favorable bioinformatic disease-altering profile,” Dr. Marlene Rabinovitch of Stanford University School of Medicine told Reuters Health by email.
“Our lead compound, Tyrphostin AG1296, is a tyrosine kinase inhibitor,” she said, “but its mode of action in reversing PAH is related to its activation of the deficient BMPR2 receptor signaling pathway, and its induction of genes that restore normal vascular function and regeneration while repressing genes that contribute to pulmonary hypertension.”
As reported in Science Translational Medicine, Dr. Rabinovitch and colleagues generated endothelial cells using iPSCs from six patients with PAH. They treated the cells with 4,500 compounds and analyzed data from publicly available databases, searching for compounds that could improve cell survival.
The screen revealed that AG1296 was associated with an anti-PAH gene signature, and that it suppressed several genes associated with PAH, supported cell survival, and inhibited the spread of smooth muscle cells.
AG1296 also induced the regression of PA neointimal lesions in lung organ culture from three patients, reduced right ventricular systolic pressure, reversed occlusive changes in blood vessels in a rat model, improved vascular function, and outperformed imatinib and other tyrosine kinase inhibitors tested as potential treatments.
The authors state, “Our studies show the value of combining iPSC-derived patient-specific vascular cell functional assays with in silico analyses to identify promising PAH drugs.”
Dr. Rabinovitch added, “We are looking forward to seeing this new agent (Tyrphostin AG1296) evaluated in patients for reversal of PAH. We will need a partnership to develop it, but with such a favorable profile for PAH and for resistant cancers, we are at a loss as to why it has not been already developed for the clinic. There does not appear to be any toxicity.”
Dr. Hina Chaudhry, Director of Cardiovascular Regenerative Medicine at the Icahn School of Medicine at Mount Sinai in New York City commented in an email to Reuters Health, “Overall, I believe this is a very promising approach to identifying drug candidates for PAH and a host of other conditions. The only caveat is that a small animal study is used for the validation and it would be exciting to see if the results are promising in a large animal model, as well.”
SOURCE: https://bit.ly/3hfGqPC Science Translational Medicine, online May 5, 2021.
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