A new Porcn inhibitor that was developed for the treatment of cancer has surprised scientists by having an unintended effect on cardiomyocytes, suggesting the treatment could also be used to help patients recovering from heart attacks reduce fibrosis and improve heart function rapidly.
Some parts of the body – the gut lining and blood cells for example – are constantly renewed throughout life. Other parts of the body do not renew, such as the heart.
Following a heart attack when the heart is damaged, the tissues in the heart cannot regenerate. While the heart does heal, the scarred tissue cannot function as well as healthy heart tissue. A considerable amount of research is focused on the Wnt signaling pathway – Wnt signaling molecules are an essential part of the tissue regeneration process.
Wnt signaling molecules are essential for tissue regeneration although they are known to contribute to cancer. Interfering with Wnt signaling could potentially be used as a treatment for cancer.
When developing the new drug, researchers looked at a specific enzyme known as the porcupine (Porcn) enzyme, which is essential for the production of Wnt proteins. The enzyme gets its name from studies on fruit flies, which resemble a porcupine if they do not have the gene for the enzyme.
Researchers hypothesized that a drug that inhibited the Porcn enzyme could be used to control Wnt molecules and combat cancer. However, while testing the new Porcn inhibitor, the researchers noticed a number of side effects, many of which had been predicted, but one had not. The drug caused the number of dividing cardiomyocytes to increase slightly, suggesting the drug could also be used in regenerative medicine, in particular, the regeneration of heart tissue.
To test the drug, Associate Professor of Cell Biology at UT Southwestern Medical Center, Dr. Lawrence Lum, and his team induced heart attacks in mice and administered the Porcn enzyme inhibitor. The team found that following treatment with the drug, mice hearts pumped blood twice as well as those in the control group.
Treatment with the drug also decreased fibrosis. Scarring of the heart following a heart attack can cause the heart to increase in size and can trigger heart failure. While the formation of scars offers an immediate benefit, they adversely affect long term heart function. Any reduction in fibrosis could result in improved outcomes for heart attack victims.
Dr. Rhonda Bassel-Duby, Professor of Molecular Biology and Associate Director of the Hamon Center for Regenerative Science and Medicine, said “Our lab has been studying heart repair for several years, and it was striking to see that administration of a Wnt inhibitor significantly improved heart function following a heart attack in mice.” Dr. Lum said, “We think we have an agent that can temper this fibrotic response, thus improving wound healing of the heart.”
Treatment with the porcupine inhibitor causes several unpleasant side effects. If the drug is used for the treatment of cancer, it must be administered for a long period; however, only short term use would be required following a heart attack, reducing those unpleasant effects.
The team now hopes to move to clinical trials involving short term use of the Porcn inhibitor on patients suffering from heart disease. The trial is expected to commence within a year.
The paper – Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist – has recently been published in the journal, Proceedings of the National Academy of Sciences.