Meet the Experts:

Learn what a researcher at the forefront of cardiac regeneration research has to say about cell-based therapies.

January, 2024

Dr. Nakamura is Director of Preclinical Research at the UW Medicine Heart Regeneration Program. This translational research focuses on pluripotent stem cell-based cardiac remuscularization therapies using various preclinical models to optimize the efficacy, safety, engraftment, and maturation of cardiomyocyte transplantation through novel genetic, metabolic, immunomodulatory, antiarrhythmic and delivery strategies.

We are pleased to share an interview with Kenta, who kindly shared his thoughts about his research with us.

What are the practical implications of your research?

Following a heart attack, the loss of billions of cardiomyocytes (heart cells) occurs, and the heart is unable to naturally regenerate this lost tissue. Currently, once it’s lost, it cannot be recovered.

Our aim is to utilize ex-vivo cultured stem cells in a bioreactor to generate authentic cardiac monocytes, with the intent of replacing the damaged tissue resulting from a heart attack.

As a clinician, how did you become involved in research?

My interest in medicine has always been intertwined with a desire to explore uncharted territory through research. Even though I contemplated focusing solely on research at times, I found myself drawn to the bedside, directly caring for patients during long hours at the hospital. However, this also fueled my desire to return to the laboratory and engage in research activities.

I’ve hopefully found a nice balance between the two, and I’ve always tried to pursue both at the same time.

I was drawn to heart attacks because, typically, they’re quite treatable. In an hour or so with your team, you can open a blockage and really help the patient, and that’s tremendously gratifying. But I also know that there are patients that we can’t help in that way, which is where the research comes in. I’m lucky to be part of these research projects that could be groundbreaking for treating these cases. The majority of heart attacks lead to some degree of permanent damage to the heart and this is part of the goal… not just treat the heart attack but prevent or reverse long term damage as well.

What is the advantage of collaborating with both clinical and preclinical teams?

Collaborating with both clinical and preclinical teams is incredibly beneficial. As a clinician, I joined the group early in the process, helping to define our objectives and pinpoint the challenges to reaching our ultimate goal of a novel therapy. While the overarching goal was clear – to treat heart failure and heart attacks – we had to identify specific obstacles, such as arrhythmias and immunosuppression, that stood in the way of achieving our goals.

For instance, when we initiated the cell replacement therapy program for heart attack patients 7 years ago, we identified potential safety concerns related to arrhythmias. Through the utilization of tools like emka’s ecgAUTO software, we got a head start in recognizing and managing this complication but also gained valuable biological insights on how to treat them.

Can your research be directly applied to patients?

Our aspiration is that the research we are conducting will eventually translate into therapies for patients. We are not talking about incremental improvements but rather revolutionary therapies that will completely change how we practice medicine.

In the future, will your therapy be administered immediately after a heart attack or over an extended period?

The timing and administration of our therapy will depend on various factors, primarily the expected benefits and risks associated with the treatment. The other part of this answer is we do not completely know yet the optimal patient or conditions for cardiac cell therapy.

Is your research applicable to other heart conditions besides heart attacks?

While our focus is primarily on heart attacks, there are several other heart conditions, such as nonischemic cardiomyopathies, that could potentially benefit from cell replacement therapy. However, our initial emphasis is on addressing the most prominent and well-defined indication, which is heart attacks. Other research groups are exploring the application of this therapy for congenital heart diseases in infants or young adults born with insufficient heart development, such as hypoplastic left heart syndrome.

What about regenerating the vascular supply for the heart?

Emerging gene therapies are being developed to stimulate the regrowth of blood vessels, which could complement our efforts to replace heart cells.

How do you address the issue of scar tissue?

There are innovative gene therapies targeting fibroblast cells responsible for scar formation. Additionally, we are exploring combination therapies that involve both cell replacement and anti-fibrotic treatments.

Why have you chosen to work with pluripotent stem cells?

Pluripotent stem cells have been selected because they allow the generation of genuine cardiomyocytes which can integrate with the host and offer long-term durability. When you are trying to replace a billion lost cells, the cells you translate have to stick around.

What immunological risks are associated with using pluripotent stem cells?

Most of our experiments were conducted using a xenograft model, where human cardiomyocytes derived from stem cells were transplanted into non-human subjects. This approach was primarily for practical purposes, ensuring cell grafting and survival.

However, more recently, we have been working with an allogenic system, transplanting monkey cardiomyocytes into monkey hosts, which closely simulates a clinical scenario. In these cases, we have gathered data indicating that we can significantly reduce the amount of immunosuppression required, lower than what patients receive during whole heart transplants. These patients can live decades with their new heart on immunosuppression.

Other technologies are also exploring ways to immunologically cloak stem cells, making them essentially invisible to the recipient. However, this approach raises concerns about uncontrolled cell growth and the potential for tumor formation.

Is cell persistence essential for long-term therapeutic benefits in heart regeneration?

My bias is that yes, cell persistence is essential for long-term benefit when you are replacing lost cells, however, this remains uncertain. Stanford University is currently conducting a trial where they administer stem cells, such as cardiomyocytes, to patients and allow the cells to be rejected after a short period of immunosuppression. The hope is that most of the therapeutic benefit would have been achieved by that point.

Is there a direct correlation between the number of cells administered and the success of the therapy?

We do not have a definitive answer to this question at this time. In our experiments, we have administered large doses of cells, up to 750,000 cells, which is considerably higher than typical cell therapy injections into the heart. We have observed some dose-dependent effects, particularly in terms of arrhythmias, with higher doses leading to more severe arrhythmias. However, we have not yet conducted dose-finding studies to find the optimal dose for safety or efficacy.

How have gap junctions been characterized in your research environment?

We have examined gap junctions at one month and three months following transplantation. Over time, we have observed that the transplanted cells progressively integrate with the host heart, including the development of connections and gap junctions. Initially, the stem cells we transplant are relatively immature, but after about a month, we observe robust electrical coupling and functional synapses.

The order of operations in pacing the heart is highly specific. How does this factor into your research, and have you explored injuries in different locations?

Our research has primarily focused on addressing the most common type of heart attack that leads to significant complications, which typically results in a large infarct in the front of the heart. This anterior wall significantly impacts the heart’s pumping function. We have not extensively explored heart attacks in other, less important locations of the heart.

Do you collaborate with other groups in the same field?

We have established numerous academic collaborations, including partnerships with the heart regeneration program at the University of Washington. We also collaborate with various teams within our own university and have connections with the National Institutes of Health (NIH).

On the clinical front, we have conducted early-phase clinical trials for gene-based therapies. I hope to see more trials involving cell-based therapies, but the are intimately connected. Collaboration is crucial, especially for combining multiple therapies to address various aspects of cardiac treatment.

Why did you choose a particular animal model for your research?

Historically, much of the research in this field was conducted using mice, rats, and guinea pigs. However, these models were not suitable for studying the type of arrhythmias we observe in cell therapy. In fact, early data in rodents indicated that our cells may actually prevent arrhythmias, but when tested in pigs, we observed quite the opposite, sudden deaths due to fatal arrhythmias. This highlighted the need for a more clinically relevant model. In pigs, we have a model that closely resembles human anatomy and physiology, making it a suitable choice for our research. Non-human primates are essentially for understanding the immunological considerations of cell therapy and remains the best model for demonstrating efficacy.

How long have you been an emka user?

Since 2017.

How did our easyTEL+ implants and software help in improving the translatable reproducibility of your research?

There are a number of products out there, where you can acquire signals from an animal (both internal and external systems). What we wanted to do was really understand more than just simple things like heart rate, which required a more sophisticated implantable system.

We work with novel arrhythmias that have never existed in nature, and that’s where emka TECHNOLOGIES has been helpful specifically, being able to phenotype the arrhythmia beyond a basic level. That’s where I found a lot of satisfaction and a lot of scholarship. We would have not been able write some of our papers, if we didn’t have that phenotypic definition.

What’s next for your lab in your research?

There are a lot of questions that are still pending, about the dose or the timing of the therapy. There are fundamental questions about how safe we can make this therapy. We recently had a paper (Silvia Marchiano et al. 2023) describing how we genetically engineered the cells, to essentially not have arrhythmia. We are at the point where in the next year or two, we would like to be able to enrol in a first early phase trials.

We were the first to do this type of work. There are now three groups that I know, that have transplanted some cardiomyocytes into patients at very low doses, nowhere near the doses that we work at. On our side, we are perhaps little overly cautious. However, we want to fully understand the potential safety issues and make sure it’s safe. I see this as a collaborative effort, and it’s not a race.

Any specific recommendations, to finish with?

I appreciate that emka TECHNOLOGIES connected me with groups working on similar studies. Indeed, this work is already really costly and difficult, and I don’t think that we need to make it harder by not sharing protocols and insights. So my recommendation when starting in this area, would be to not hesitate to search for collaborations, and to contact us.

It took us a few years to establish our model, and we would be happy to have others work in this space. Naturally, there is this competitiveness, but I would much rather collaborate, and we’ll get to the finish line faster together, than to see other groups struggle unnecessarily.

THANK YOU, Dr. NAKAMURA, FOR THIS INTERVIEW!

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