Potential Medication Target for Deadly Heart Disease – ScienceDaily

The study found that the chemical inhibition of the pathway corrected the effects of the mutation in the cardiac cells derived from the patient in a laboratory antenna. The researchers accomplished this with drugs already approved by the Food and Drug Administration.

The results, which will be published online on July 17 in Nature, suggest that existing drugs may one day be reused to treat dilated cardiomyopathy. More generally, the study shows how cardiac cells derived from the patient can help scientists better study the heart and select new drug candidates.

"With 10 milliliters of blood, we can manufacture clinically-usable amounts of your heart cells in a dish," said lead author Joseph Wu, MD, PhD, director of the Stanford Cardiovascular Institute and pioneer of the technique. "And if you tell me that you're taking medications for your heart – like beta-blockers or statins – we can add that to see how it affects your heart.It's the beauty of this approach."

The researchers studied cardiac muscle cells from patients with a genetic mutation badociated with dilated cardiomyopathy. Cardiac cells with a mutation in the lamin, which are part of the nuclear envelope, have failed to beat properly – just as in patients with the disease. Scientists discovered that the defect was due to an increase in platelet-derived growth factor pathway. This pathway is important in the formation of blood vessels and normally only occurs when the heart is forming or is under stress. Treatment of cardiac cells with existing inhibitors of the pathway has restored regular and rhythmic beats.

Do not stop the pace

In dilated cardiomyopathy, the main pumping chamber of the heart, the left ventricle, expands so much that the heart can no longer beat regularly. Patients suffer from shortness of breath, chest pain and, in severe cases, sudden and fatal cardiac arrest. About 1 in 250 Americans suffer from a form of dilated cardiomyopathy whose exact cause is not known, although 20% to 35% of these cases occur in families.

Previous studies have established a correlation between lamin mutations and familial dilated cardiomyopathy, but this seemed to be a strange connection. The lamin is part of the nuclear envelope, a structure that separates DNA from the rest of the cell and regulates the movement of molecules in and out of the nucleus – it is not an obvious candidate for the regulation of cardiac function.

"We were perplexed," said Wu, Ph.D. Simon H. Stertzer, and professor of medicine and radiology. "Why would a mutation in a nuclear envelope protein not involved in core compression, such as the sarcomeric protein, or in the electrophysiology of the heart, such as an ion channel, lead it to? to dilated cardiomyopathy? "

To solve this mystery, researchers had to study laminar mutation in cardiac muscle cells. Extracting a tissue sample from the patient's heart, an invasive medical procedure, was not a good option. Mouse tissue was another possibility, but discoveries in mice do not always stand up in humans.

Instead, scientists generated heart cells by going back to skin cells derived from the patient to produce induced pluripotent stem cells, which can become any specialized cells present throughout the body. Although the researchers used skin cells in the study, Wu said the same technique could also be used with 10 milliliters of blood, or about two teaspoons.

The cardiac muscle cells developed in a dish pulsate rhythmically, just as in the body. But cells of members of a family with lamin mutations and a history of dilated cardiomyopathy have an unusual rhythm and have irregular electrical activity. The defect could be corrected by replacing a normal copy of the gene with genetic modification technology. The introduction of the mutation into healthy patient cells also caused an irregular rhythm of these cells. Cells bearing the laminar mutation had abnormal levels of calcium, a key ion that regulates muscle contractions.

Find the rhythm

As part of the nuclear envelope, Lamin interacts with a form of compact DNA called heterochromatin. Interestingly, the researchers found, by various DNA sequencing techniques, that cells with the laminar mutation had fewer heterochromatin regions. Since the packaging of DNA affects the choice of activated or deactivated genes, the researchers examined gene activation patterns to determine the mechanisms that have deteriorated in the cells carrying the genes. the mutation and what they could do about it.

"Although we have done all this sequencing and other experiments, without a specific target, we can not provide the right treatment," said lead author of the study, Jaecheol Lee, PhD , a former postdoctoral fellow who is now an adjunct professor at the School of Pharmacy at Sungkyunkwan University in South Korea.

They found nearly 250 more highly activated genes in mutated cells than in normal cells. Many genes were part of the Platelet-derived Growth Factor (PDGF) pathway. When the researchers tested the heart tissue of patients with dilated cardiomyopathy with a lamination mutation, they found signs that the same pathway was activated.

But did the activation of the PDGF path cause abnormal rhythms or the reverse? To test this, the researchers treated cardiac cells with two drugs, crenolanib and sunitinib, that inhibit a key PDGF receptor. After treatment, cardiac cells with laminar mutation began to beat more regularly and their gene activation patterns were more consistent with those of healthy donor cells.

Both of these drugs are approved by the FDA for the treatment of various cancers. But previous work by Wu's team has shown that drugs can damage the heart in large doses, making it essential to find the right dose or a safer alternative.

The present study fits in as part of a broader effort by researchers to use these patient-derived cells in a box to screen for and discover new drugs. This is why the Wu laboratory has generated cardiac muscle cells of more than 1,000 patients, including Wu, his son and daughter.

"Our post-docs took my blood and differentiated my pluripotent stem cells into brain, heart and liver cells," said Wu. "I'm asking them to test some of the medications I may have to take in the future."