Stem Cell Breakthroughs In Congenital Heart Repair

Timothy J. Nelson, MD, PhD

It’s great to be with you.

Joel Kahn, MD, FACC

Just give us, like, a couple of minutes on your path. I don’t know if you’ve trained as a cardiologist. I apologize for not knowing that. But, how did congenital heart disease catch your imagination and intention?

Timothy J. Nelson, MD, PhD

I was training to be a cardiac surgeon, as I was training to be when I was in medical school. At that time, regenerative medicine and stem cell biology became the hot topic of the day when I was in medical school, and I decided to make this a career choice as we went along the way in my training at Mayo Clinic, and now we are running HeartWorks and a physician-scientist at Mayo Clinic with a vision of how to apply the next technology to not only rebuild the heart but also preserve and protect hearts for the longevity that we expect our hearts to live through. as the regenerative capacity of the heart is limited. Science and technology are evolving not only from the things that we do to ourselves—our food, our diet, our exercise—but also from the medicines and treatments that we take. How does that affect the ability of our heart to regenerate? That’s become my passion, and that’s become my career trajectory: to try to be a physician-scientist, to make this reality a reality for us today and not for the future generation.

Joel Kahn, MD, FACC

Incredible. Let me ask you the last question first. I’m going to interview you in 2034, ten years from now. You’re telling me what hard work has been achieved for children and some adults who have survived congenital heart disease until adulthood? What would you like to say our company has accomplished in advancing the care of people with congenital heart disease?

Timothy J. Nelson, MD, PhD

In ten years, it will be routine for various types of cell-based regenerative medicine to be used during heart surgery and catheter-based surgeries. It will be an adjunctive therapy, which means that we added on to the therapies that were already doing the operations that people will need. We will start with the sickest of the sick patients, the patients who are in the greatest need, and the complex congenital heart patients. We will be using regenerative technologies to rebuild the heart. The goal will be to be able to touch your heart no matter what. You’re born strong enough that you won’t need to have your heart transplanted or removed from your body. We’ll be able to make it strong enough that it will be able to live up to the demands of life. That’s where this technology starts in the next ten years. That’s what our focus will be. But you can quickly imagine where this technology will be available to anybody who has pump failure or heart failure. Despite the best treatments and a healthier lifestyle, some patients will have risk factors that will require additional therapies. The regenerative medicine technology that’s available to us today will become more widely available in the next decade.

Joel Kahn, MD, FACC

We’ve got a very bright future. We’re talking about, again, complex congenital heart disease. There are children born with one ventricle pumping instead of two, for example. I know survival may be very limited. We’re hearing about heart transplantation. We know there have been a few people who have attempted, in adults, to turn a pig heart into a human, having had very long survival. But it’s still early in the game. Do you think we’re going to be able to 3D print parts of the heart or maybe an entire heart? And what do you envision? How are you going to regenerate the abnormal heart anatomy in these complex cases?

Timothy J. Nelson, MD, PhD

Here’s our vision at HeartWorks. We built hearts. We believe that we can use your cells, and your body, to regenerate your heart muscle in the lab and transplant your heart muscle back into your heart to make it bigger, better, and stronger. The hope is that your heart will be able to be rebuilt, to be strong enough, and to never have to be heart transplanted. Or we don’t even need to do a 3D-printed heart because our vision is that we can rebuild your heart from the inside out. The way we do that is to start with a piece of your skin. We engineer it into stem cells. We make it into your beating, contracting heart muscle, and then we surgically transplant or implant it into your heart to make your heart bigger and stronger. Now, there are multiple form factors that this is going to take in the future, but it’s suffice to say it’s like gardening or farming. We are planting seeds that can grow new heart muscle. We are doing that right now. Our clinical trials are open, and in the next ten years, we’ll be able to show who’s going to benefit the most from this type of technology and how to make it more widely available. If we do, our job will eliminate the need for heart transplantation, the need for pig hearts, and the need for 3D-printed hearts because we’re rebuilding your heart to meet the demands of your body and your lifestyle.

Joel Kahn, MD, FACC

That’s an amazing vision for HeartWorks Inc. I’m no expert on what you do, but I read a little in general. We take a fibroblast, expose it to Yamanaka factors, and turn it into a pluripotent stem cell.

Timothy J. Nelson, MD, PhD

Those are some of the big words you use there.

Joel Kahn, MD, FACC

In big words, I know I listen to David Sinclair and then I apologize.

Timothy J. Nelson, MD, PhD

That’s 100% right. The best way I can describe it in layman’s terms is that we take a plug of your skin out like a biopsy. If we were going to do a skin biopsy or remove a mole from your skin, we would like to start with skin cells. We take the glue—the mortar that holds your skin together. They’re called fibroblasts. The glue and mortar that hold your skin together can grow rapidly. When you put it on plastic plates in the lab, this grows out, and we get hundreds and thousands of millions of cells that can grow in the lab. These cells are then the starting blocks that we reprogram back into what looks and feels like a stem cell, or, to use the word, pluripotent. These are called induced pluripotent cells. We are doing that through a repro-naming process. We don’t create an embryo. We don’t destroy an embryo. They’re your cells. They’re genetically identical to you. But they now start thinking and behaving like they did when they were embryos. That means we can now train them to become any tissue in your body, but the one we like to train them to become is heart muscle. The way we know it’s heart muscle cells is that they’re beating and contracting under the microscope, and they’re contracting at the same rate that your heart can track in your body. This then becomes the material that we’ve manufactured and can be used for surgical transplantation back into your body, which means your body won’t reject it and your body won’t recognize it as foreign tissue because it’s genetically identical. It started with your body.

Joel Kahn, MD, FACC

That is so fascinating. Tell us about something like a clinical trial. Who’s a candidate right now in a trial that you’re doing, or several trials?

Timothy J. Nelson, MD, PhD

We’ve had five ongoing clinical trials to get to this point. The current clinical trial that we’re conducting is on patients who were born with single-ventricle congenital heart disease. These are patients who have a missing heart on the side. They’re the most severe forms of congenital heart disease. There are probably 10 to 20000 of these patients living today in the United States. These are the patients who are eligible for the world’s first clinical trial that I just referenced, where they will make their cells and be able to transplant their heart muscle cells back into their hearts. They have a five-horsepower engine. Our goal with this approach is to make their horsepower a 10, 20, or 50 horsepower motor, to rebuild it, to make it strong enough. We’re starting with the patients who have not very good options or no options. They’re the patients who have very sick hearts. These are the hard patients to find right now to be part of clinical trials. As we prove that this technology can be safe and effective in that population, we’ll start envisioning how we can bring it to more patients more rapidly.

Joel Kahn, MD, FACC

That’s incredible. This is something you grow in the lab, but you have to take these generally young children to the operating room to apply these sheets of the now-beating heart muscle to their hearts.

Timothy J. Nelson, MD, PhD

The clinical trial that we’re starting with will be for adults only. We’ll be moving it to kids when the time is right when we have more data to justify that. But in partnership with the Mayo Clinic in Rochester, Minnesota, and under the oversight of IRBs and the FDA, this is adult patients with congenital heart disease that we’re starting with today.

Joel Kahn, MD, FACC

A little easier to start on a big target than start on a pinhead. makes some sense. The longevity of these adults is quite limited. I can understand that you have a separate company, but I don’t know if it’s a company or an organization, and I’m going to say it wrong because it’s a mouthful, ReGen Theranostics. That’s a little different from what we were talking about. Does HeartWork Inc. have a physical location? Is there a biological lab that is called HeartWorks, Inc.?

Timothy J. Nelson, MD, PhD

HeartWorks, Inc. is our nonprofit clinical-stage company that is raised with philanthropic support, aligning academic institutions to work collaboratively to show that this technology can be done safely and efficiently. So within that non-profit structure of HeartWork, we also have a wholly owned subsidiary known as ReGen Theranostics, that’s where we are, where we’re holding the IT, and we’re building the manufacturing capabilities to be able to scale this to other diseases such as dilated cardiomyopathy or ischemic heart disease, or patients that are adults with more common conditions. We do envision a day when we’ll be able to expand our clinical trials beyond the congenital heart world of HeartWork and bring it to a larger patient segment using the infrastructure that we’re creating in the region. It’s an interesting, unique hybrid model between a nonprofit academic environment and for-profit scale-up manufacturing to be able to move efficiently and cost-effectively to bring this type of technology to as many patients as possible.

Joel Kahn, MD, FACC

When do you think the first adult with congenital complex heart disease, single ventricle, might be in an operating room getting this implant from ReGen Theranostics?

Timothy J. Nelson, MD, PhD

We’re talking about the end of 2023, right now as we sit here and we are open for enrollment in this clinical trial. So we envision that through 2024 and 2025, we’ll be enrolling patients and executing this clinical trial. The clinical trial is open, and the permissions are all intact. We are at the clinical stage of the development of this. We’re recruiting patients that meet the inclusion criteria today to be able to make this a reality.

Joel Kahn, MD, FACC

How long is the lab process before a patient gets scheduled for the operating room? Is it taking months or weeks to go from this skin biopsy to another tissue to take them to the operating room?

Timothy J. Nelson, MD, PhD

It’s a very perceptive question that you’re asking right now. It’s not short. It takes us nine months to manufacture this process. Let me tell you why. Being the first in the world that we’re doing this, there’s biology involved in taking the cells through this process that we simply can’t shorten. But we also take a lot of extra steps to make sure that the product is safe and that it doesn’t have infections or contamination. We do all the testing in those nine months before we release it for surgical treatment. We do many other products. We’ve treated hundreds of patients out of our lab with other cell types. So we have good processes in place to be able to make sure that this can be done safely and reproducibly. So with this world’s first clinical trial, it has been a long time. It’s one product for one patient, and we can probably shorten that quite significantly as we scale it and as we start doing it for more patients in the future. But right now, it is a nine-month process. Every day, these cells are taken care of in the lab to make this happen.

Joel Kahn, MD, FACC

How big is the is the team? Again, the team would be under the ReGen Theranostics. 

Timothy J. Nelson, MD, PhD

We work side by side, ReGen Theranostics is wholly owned by HeartWork right now. We like to think of everybody as working for our congenital heart mission today. We have nearly 60 people, and across the whole team, it’s a seven-day-a-week manufacturing process in-house. We don’t outsource that to anyone. So we’re building the infrastructure to be able to do this type of work with our team from the ground up. That makes our HeartWork very unique and very different. But it’s important to be able to accelerate the learning of what it takes to do this type of technology and to be able to bring it to a larger market more quickly.

Joel Kahn, MD, FACC

Where do you think the first surgery will happen? Will it happen at the Mayo Clinic?

Timothy J. Nelson, MD, PhD

We have only one site open for this protocol right now. That said, the Mayo Clinic is in Rochester, Minnesota. Our clinical colleagues in the Department of Surgery and Cardiology are working with us to make this happen.

Joel Kahn, MD, FACC

This has been exciting. everybody listening again, this is a Reversing Heart Disease Summit. We talk about reversing high blood pressure, reversing cholesterol, reversing diabetes, and reversing atherosclerosis. But we don’t talk a lot about reversing commonplace congenital heart disease. You’ve painted such an exciting future for us that, if anybody were to know a family relative with complex congenital heart disease, how do they contact somebody in the research department?

Timothy J. Nelson, MD, PhD

The easiest place is to go to our web page webuildhearts.org, and there’s contact information on that page that will direct you to us to get you more information.

Joel Kahn, MD, FACC

That’s exciting.  It took me over to heartworksinc.org, but it is right there. We built hearts. I have looked at your other websites. I apologize. You have a nice association with Porter family vineyards. I have to give you a shoutout for picking a nice, uh, a nice red varietal to raise money. But one in 100 children. That’s what we say 1% of babies born are born with congenital heart disease. It’s common. There will be many that will be potentially able to benefit from this down the road. It all takes time and careful research. Of course, you accept donations, right?

Timothy J. Nelson, MD, PhD

HeartWorks is a nonprofit that does all of this work for these early-phase clinical trials. That’s 100 percent right.

Joel Kahn, MD, FACC

You never know if Elon Musk or Jeff Bezos will sign up for a summit. They might ring your email right away and make it in. Tim Nelson, uh, professor of regenerative medicine, Mayo Clinic. Good deal. don’t go anywhere for our general listeners. I hope you’ve enjoyed this as much as I have. Fascinating, futuristic, but already enrolling. If you do go to this website, webuildhearts.com.

Timothy J. Nelson, MD, PhD

Dot org.

Joel Kahn, MD, FACC

webuildhearts.org. You’ll see pictures of babies in the science and the scientists and the team. Please go over there. But don’t go anywhere near Doc Nelson. I’m going to hang on to you for a couple of minutes for our premium listeners and just go a little deeper on a couple of topics. thank you.

Timothy J. Nelson, MD, PhD

Thanks for having me.

Joel Kahn, MD, FACC

All right, Doctor Doc team you let it out. This little jabber right now, we’re going to go back for another few minutes with Dr. Nelson here. All right, Dr. Nelson, thanks so much for staying with us. Let’s just go a little deeper. You said a couple of things during the first part of the interview, and I wanted to just go a little deeper with it. More common and complex congenital heart disease, and no less compelling is the large market of adults with weak hearts, weak hearts from a previous large heart attack or suffered a heart attack, or weak hearts from a viral infection. Weak hearts from a kind of unknown cardiomyopathy, as we call it. that may be further down the road. But it’s such a big market, of course, leading to congestive heart failure, the need for defibrillators now, and sometimes a concise life span with a reduced quality of life. What is the leap in technology from approaching complex congenital heart disease now to the next phase of starting to use it as an alternative to heart transplants or pig transplants in humans with weak hearts and advanced congestive heart failure?

Timothy J. Nelson, MD, PhD

The thing that makes us most concerned with that leap is the risk of arrhythmias, right? We are rebuilding the heart with electrically active tissue. So when you have a patient with a heart attack and a major loss of heart function, many of them are dealing with multiple forms of arrhythmias, and these cells could potentially exacerbate that. We’re working through how to reduce that risk of arrhythmias, and we’re working through what the right models are to be able to test that and gain confidence that this electrically active tissue that we’re engineering does not cause additional problems with patients that have had heart attacks. That’s likely the most difficult patient to get after. But as you said, there are other patients with viral myocarditis, dilated cardiomyopathy, or other genetic forms of heart disease who have weak heart muscles that are less affected by scar tissue. These are the patients for whom this technology becomes relevant as the second tier. The first tier will be the congenital heart. The second tier will be nonischemic cardiomyopathy. Then we do have to be able to rebuild the scar tissue that has formed in patients who have had heart disease. But the thing that I get most excited about is that we can start predicting and intervening earlier than we ever thought possible. By having access to technology like this, how do we bring technology to patients in a preventative strategy rather than trying to rescue them from ultimate failure at a crisis moment? So this is where personalized, manufactured tissue becomes exciting, is at-risk patients. Patients at the earliest stages of forming a weakened heart muscle start rebuilding it with multiple doses at a prescribed regimen. When you show that this can be done safely and efficiently, that changes the paradigm of how we think about it. Getting away from crisis mode, thinking of a heart transplant, and getting towards more longevity, rebuilding, and strengthening the heart—that’s where this technology truly becomes a game changer.

Joel Kahn, MD, FACC

That is such an exciting future. The challenges that you have to bridge will be very interesting to see and hopefully work out sooner rather than later. I just hope you made another statement during the first part of our interview that you have a team of 60 and you’ve treated or you’ve been involved in other conditions, other patients. Maybe I didn’t understand that. But other than this push for complex congenital heart disease, what does ReGen Theranostics mean? What’s the rest of the scope of what they’re working on?

Timothy J. Nelson, MD, PhD

So when we started, 2013 was the first patient we treated. That was a decade ago, using tissue collected from the cord blood at the time of birth. babies with congenital heart disease diagnosed in utero before they were born, we were able to collect their autologous cord blood and process those cells. We’ve used that in many, many protocols. We’ve done phase two B clinical trials. We did a 50-patient controlled trial using that product, and we’re following those patients right now. To complete the follow-up on that. of that as fertilizers. The cord blood itself does not cause new heart tissue to form, but it can fertilize the heart. In this case, we were treating three-month-old infants with congenital heart defects at the time of open heart surgery. We injected the cells at the time of operation to try to use the fertilizers in the cord blood cells to fertilize, rebuild, and strengthen the heart of a three-month-old infant. We’ve done that on over a hundred patients so far, and that’s been the pathfinder for us to develop the manufacturing, develop the clinical teams, and develop a clinical quality oversight to be able to take on the bigger project, which is this bioengineered project that we’ve talked about.

Joel Kahn, MD, FACC

This is exciting. So some of the most exciting stuff we’ve ever discussed in this segment. Thank you for your time. Thank you for your expertise. Thank you for sharing again. Just one more time for those wanting to pursue further; maybe they have a family member or friend; maybe their own heart has been damaged and they want to follow this closely. As you make further progress, tell us again where to look for more information.

Timothy J. Nelson, MD, PhD

Come see us at webuildhearts.org. You’ll find out our full story. You’ll find out ways you can engage with us. We’ve got some exciting opportunities with virtual lab tours. People can join us, and we’ll bring you to the lab. We will show you the manufacturing of the cells. You simply sign up on the website, and we’ll get you in the lab and show you exactly what we do firsthand. We’d love to have all of you join us for a virtual lab tour, and there are many other activities and educational seminars you’ll find out about on that website. We appreciate spreading the word because it takes all of us together to pull these things off. You’re helping contribute massively by sharing this story and reaching out to anyone anybody knows with congenital heart disease. Thank you, Joel, for sharing your personal story on this, because it’s connecting all of these families that make this possible.

Joel Kahn, MD, FACC

No problem. We all have to care. This will reach tens of thousands of people who may not have known much about congenital heart disease and probably knew nothing about the groundbreaking work you’re doing. Keep it up. Thank you very much. Get this project done soon.

Timothy J. Nelson, MD, PhD

We are working on it. It always moves as fast as we’d hoped.

Joel Kahn, MD, FACC

It never does.