Treating Heart Failure Through Cardiac Regeneration

P. Duc Si Dong, PhD; Mark Mercola, PhD


April 01, 2013

Editorial Collaboration

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P. Duc Si Dong, PhD: Hello. Welcome to this segment of Developments to Watch from Sanford-Burnham Medical Research Institute and Medscape. I'm Dr. Duc Dong, Assistant Professor in Sanford Children's Health Research Center at Sanford-Burnham.

Today, I will be talking with my colleague, Dr. Mark Mercola, Director of our Muscle Development and Regeneration Program, about the work that he and his team are doing in developing a new approach to replace diseased or damaged cardiac muscle tissue. As we will see, Dr. Mercola's laboratory is looking for small molecules that can be used to trigger cardiac tissue regeneration.

Mark, what is the advantage of your regenerative approach vs current therapies?

Mark Mercola, PhD: Current therapies [for heart failure] try to "unload" the heart -- make the heart work less against blood pressure. They work by blocking the renin-angiotensin system or altering response to the adrenergic system. What we're trying to do is regenerate the heart muscle that's actually lost in heart failure; by doing so, we would be increasing the heart's own fundamental pumping ability. In this way, you'd make the heart stronger, and you'd be restoring the cells that are lost during heart failure.

Dr. Dong: Other people are trying to make cardiac cells from stem cells to transplant them into a patient. How is your approach different?

Dr. Mercola: Our approach is fundamentally different. In a cell-based therapy, the idea is that you would be creating heart muscle cells or other heart cells and transplanting them into the heart. Those cells would have to take up residence in the heart and, by doing so, improve the pumping ability of the heart.

In our case, we want to produce a small molecule or an RNA therapeutic or other sort of drugs that would stimulate the heart's own ability to regenerate. The question of whether the heart regenerates has been very controversial. But now it is widely appreciated that there is a limited ability to regenerate. So we would like to identify drugs that would specifically stimulate that regenerative capacity.

Dr. Dong: There are some patients who, if you do help them ease the work of their hearts, can actually recover from a heart attack. Is this related to what you're talking about?

Dr. Mercola: Yes. In cases where you unload the heart, often with a mechanical device, patients will recover some ability, some pump function. This is one of the bits of evidence that teaches us that the heart can recover after injury. What we would like to do, of course, is make that much more robust.

Dr. Dong: There are so many small molecules to screen through. How do you go through so many?

Dr. Mercola: We have a large, high-throughput screening capacity here at the Institute. When we have an assay, we're able to robotically screen many hundreds of thousands of molecules to look for those compounds that have the desired activities. In many cases, however, the assays are not capable of being screened directly against such a large collection of potential drugs. So, using the screening approach, we try to understand the basic processes that are controlling the function we're after, such as contractility of the heart.

To give you an example of this approach, we have an assay that looks directly at the contractile function of cardiomyocytes, the heart muscle cells. We've been able to screen the entire genome's worth of microRNAs to discover microRNAs that affect contractility and the heart.

As you know, microRNAs regulate many processes -- many proteins and many genes within the organism. We found a few that actually suppress contractility in these cardiomyocytes; of those, several are upregulated during human heart failure. We've gone on to develop an RNA therapeutic, a potential drug, that blocks the function of these detrimental microRNAs. This molecule is performing very well in preclinical animal trials. In these animal trials, we establish heart failure, and the RNA therapeutic is able to halt progression of heart failure and even revert the decline in cardiac function so that we get better pump function out of the heart.

Dr. Dong: You mentioned that you use contractile cells for high-throughput screening. Don't you need a lot of them?

Dr. Mercola: Yes. We use stem cells for this purpose. Stem cells have the ability to generate almost every cell type in the body. We direct the stem cells to become heart muscle cells. Those cells can be placed in multiwell dishes and used in a high-throughput setting. In this way, we can screen molecules directly for their ability to affect the function of heart muscle cells. That's an important advance based on a lot of work in the stem cell biology field.

Dr. Dong: Could you tell me about the molecule that you pulled out that you're really excited about?

Dr. Mercola: Yes. There's one molecule that we described recently in a Cell Stem Cell paper that inhibits transforming growth factor (TGF) beta.[1] TGF beta during heart failure is prominent because of the increased scarring in the heart. What we'd like to do is use this compound to diminish the scarring. But, most important, what we've discovered is that inhibiting TGF beta promotes the regeneration of heart muscle cells from stem cells through a mechanism in which it activates genes specifically involved in converting a stem cell into a heart muscle cell. So, the thinking is that, by inhibiting TGF beta signaling in the context of the failing heart, we could boost the heart's own regenerative capacity -- in essence, take advantage of the stem cells that are there and drive them more efficiently than otherwise to become new heart muscle cells.

Dr. Dong: How do you take the molecules that you discover to the clinic?

Dr. Mercola: The molecules that come out of the screens first need to be optimized so that we can use them in animal trials. We take the molecules into small animals first and then larger animal models of heart disease -- myocardial infarction, chronic pressure overload, or other similar models. For instance, the RNA therapeutic that I told you about has been working very well in animal models of heart failure.

The road to clinic is rather long. Obviously, pharmaceutical companies spend a great deal of time and a great deal of money in bringing a drug to market. What we would like to do at this point is produce a good molecule and have a partnership between the academic laboratory and a company in order to take the molecule all the way to the clinic.

We're optimistic that this can happen. Pharmaceutical companies are showing a great deal of interest in regenerative therapies and in the large unmet need to complement the traditional approaches of unloading the heart that we talked about earlier.

We're very optimistic that there's the will and the science behind taking these molecules forward. I think that'll be a strong embodiment of the idea that stem cell biology can give rise to novel forms of medicine.

Dr. Dong: The work being done in the lab today is the first step in bringing new treatments to the clinic. Thank you for joining us today. I hope you will join us for additional programs in the Developments to Watch series on Medscape.