Generic Molecule That Activates Mitochondrial Protein Seen to Treat PAH in Small Study

Ashraf Malhas, PhD avatar

by Ashraf Malhas, PhD |

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A generic molecule that works by activating a mitochrondrial protein, dichloroacetate (DCA), was seen in a Phase 1 clinical trial to  reduce pulmonary arterial blood pressure and improve lung function in patients with pulmonary arterial hypertension (PAH).

In PAH, cells of blood vessels adopt characteristics that are similar to cancer cells, including suppressing certain pathways within mitochondria, the energy-producing parts of a cell. This suppression dampens a natural cell process known as programmed cell death (apoptosis), and raises the rate of cellular proliferation. Cell overgrowth results in a narrowing of blood vessels.

In the study “Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients,” published in the journal Science Translational Medicine, researchers identified an enzyme that can be targeted in PAH.

They found that the mitochondrial enzyme, pyruvate dehydrogenase kinase (PDK), is elevated in cells from the pulmonary arteries of PAH patients compared to those of healthy people serving as controls. This was reversed by treating PAH  lungs ex vivo (i.e. lungs removed at transplant surgery and kept functional within the laboratory) with DCA, a PDK inhibitor.

In a four-month, open-label study (NCT01083524) conducted in Canada and the U.K., DCA was given to 30 patients with idiopathic, familial or anorexigen-associated PAH, who were already on approved therapies, had a positive effect on symptoms. The treatment reduced the pressure in pulmonary arteries and improved lung metabolism, as assessed by positron emission tomography and computed tomography (PET-CT) scans.

“This is the first time that a drug targeting mitochondria is shown to be effective in patients with PAH,” Evangelos Michelakis with the University of Alberta and the study’s first author, said in a press release.

This effect, however, was not the same across all patients. Those with variants in SIRT3 and UCP2 genes, which code for proteins that work to suppress mitochondrial function but are independent of PDK, did not respond to DCA.

“This is a great example of precision medicine, where the patients’ genes can be used to predict the effectiveness of a drug in a particular patient,” said Martin Wilkins, of Imperial College London, a study co-author.

“Another important aspect of the study is that DCA is a generic drug, and thus the study was not sponsored by a pharmaceutical company, but from public funds and donations. This means that if future studies confirm our results and show a clear and definitive benefit of DCA in PAH, we may have an affordable, cheap treatment available to all,” Michelakis said.