What is dilated cardiomyopathy?

MestroniDilated cardiomyopathy is a heart muscle disease that reduces the heart’s ability to pump. It is a disease that causes arrhythmia and can lead to heart failure. In some patients, it may lead to heart transplantation. Mortality rates have improved significantly over the past 10 to 20 years because there are very good treatments that improve patient outcomes. This is a relatively common disease, affecting 1 in 250 people. At least half of patients with DCM are thought to have a genetic cause, and genetically speaking, there are many different causes. And how those genes are present can be different. For example, there are certain genes that cause more severe disease in women and other genes that cause more severe disease in men.

Please tell me more about patient registration.

Mestroni: When we first started researching DCM, we didn’t know it was caused by a genetic condition. So we started observing that there were families where more than one person was affected. Then we started collecting that information through registries, first in Italy and then here in the United States. Since 1999, the active registry has registered well over 2,000 patients.

What did you learn about the genetics of DCM from the families you studied?

taylor: There are at least 20 genes for which there is very strong evidence that they cause cardiomyopathy, and at least 20 more that have associated evidence. Therefore, there are at least 50 genes that have been identified with varying levels of confidence for this disease. Each of these genes may have slightly different problems and mechanisms.

Have you identified potential treatments?

taylor: Because we know the genes and we have registries, we can select a specific gene and hypothesize a targeted therapy against it, a precise therapy. We’re going to be doing gene therapy this year at the University of Colorado to correct fundamental defects in patients, and I think that’s great. When I started this job, I didn’t necessarily think I was going to do that. Several gene therapy clinical trials are currently underway, which seek to actually correct genetic defects in patients, rather than in cells or mice. There are currently four gene therapy trials underway for a variety of related diseases, targeting four different genes. Starting this year, these trials are testing targeted therapies in cardiomyopathy patients with specific defects. This is something we’ve been talking about for more than a few decades, and the technology is finally mature enough to start.

A very simplistic analogy for gene therapy is that it’s a bit like Amazon coming to your door. Amazon drivers can deliver anything in Amazon boxes. For gene therapy, now that you know the driver and the size of the box you need, you can ship all kinds of different cargo with that box. Technical factors may make it easier or more difficult to utilize. For example, it is easier to deliver to the bone marrow than to the liver. However, this success means that we are not alone in the field of cardiology and that other fields are doing similar research.

This sounds like groundbreaking news. How is gene therapy performed?

taylor:That’s right! At Children’s Hospital Colorado, we do a lot of gene therapy for pediatric diseases. But outside of the field of cancer, adult gene therapy is very novel. There are several different approaches, but the approach used here is direct injection through an IV. For patients with genetic defects, gene therapy provides a properly functioning copy of a gene, essentially repairing or replacing the damaged gene. In theory, once the injections are made, these patients could be followed for months, years, or even decades to potentially correct any defects that could eventually be cured. You will be checking to see if you have provided it to them.

What are your hopes for your patients?

taylor: This is completely new, but it holds promise for identifying heart failure patients at an early stage of the disease. The disease can then be slowed or stopped, and ideally even reversed. We want to identify patients with the defect early enough in the disease process to give them drugs that truly target their effects.

What would you like others to understand about your work?

Mestroni: Outcomes An important aspect of our work at the research level is sharing data with centers around the world. By bringing all the data together, even if a single gene is rare, we have a large amount of data from which to build predictive models. This will allow us to address patient risk stratification and identify patients at risk of sudden cardiac death.

We collaborate with scientists all over the world doing the same research. The registry and its data are a very powerful tool for giving patients answers, and fundamentally none of this would be possible without the many patients who participate and support this research.

Guest Contributor: Carie Behounek is a writer specializing in health and science.