Heart failure, a leading cause of illness and death affecting some 6 million Americans, remains incurable. About half of these patients have diastolic heart failure, where the heart’s left ventricle is too stiff to relax between beats, limiting blood flow to vital organs. Current drugs largely manage symptoms without addressing the root cause.
Now Richard Nkulikiyinka, MSc, MBBChir, MRCP, and David Zebrowski, PhD, of GenKardia Inc., are developing a novel compound targeting Titin — a protein linked to heart stiffness — and taking inspiration from a surprising source: hibernating bears.
Nature’s Playbook: Bears and Heart Flexibility
Titin, a key protein in heart muscle, has two forms: N2B, which promotes stiffness, and N2BA, which allows the heart to relax after a contraction. During hibernation, grizzly bears ramp up production of N2B to keep their heart from overstretching as a result of dramatically slowed heart rates. When they awake, N2B levels fall, while N2BA levels rise again, restoring heart elasticity.
The discovery that targeting Titin N2B could help modulate human hearts' flexibility inspired the development of GKA-100, a compound with potential first-in-class status as a treatment for people with diastolic heart failure. As rates of diabetes, obesity and aging climb, the demand for better treatments is growing. Indeed, the heart failure market is projected to reach nearly $19 billion by 2034.
GenKardia also sees potential for developing GKA-100 as a therapeutic for patients with rare restrictive cardiomyopathy (a genetic disease that can affect newborns) or hypertrophic cardiomyopathy.
The promise of GenKardia's technology led to Nkulikiyinka and Zebrowski being named as a finalist team for the XSeed Award, which provides grants of up to $250,000 to New York City minority- and women-led life science and healthcare startups working on novel preclinical drug development projects. Winning teams also join the ecosystem of Cure, a healthcare innovation campus headquartered in New York City.
A Serendipitous Meeting Leads to Collaboration
The scientific journey leading to GenKardia began during Zebrowski’s time as an Assistant Professor at the Chinese University of Hong Kong from 2019 to 2022. There, he met a young boy born with restrictive cardiomyopathy, a disease that causes a very stiff heart. Nothing can be done for these infants other than placing them on life support until they are old enough for a heart transplant, and even then, they would need a matched donor.
Previous attempts to treat heart stiffness diseases took aim at RBM20, a protein that ensures the heart makes N2B. But RBM20 also regulates as many as 40 to 50 other genes, and inhibiting it is associated with significant toxicity.
Zebrowski and his colleagues explored a better approach by targeting the RNA in the heart responsible for creating Titin N2B. This subsequently led to the development of GKA-100 to directly reduce the expression of Titin N2B without affecting Titin N2BA, thus raising the N2BA/N2B ratio — much like the bear's heart emerging from hibernation.
Unlike RBM20, Titin N2B is only expressed in cardiomyocytes (heart cells), making the GKA-100 treatment highly specific, with reduced risks of side effects.
In 2023, Nkulikiyinka gave a conference presentation on diastolic dysfunction, and Zebrowski approached him with the idea to collaborate. A native of Rwanda, Nkulikiyinka had gone to medical school in Germany and the United Kingdom. During his internal medicine residency in the UK, he repeatedly witnessed how cardiovascular emergencies could affect people's lives.
At the same time, Nkulikiyinka was curious about medications that could help patients get back on their feet, and he became interested in learning more about drug discovery.
"I decided to do a stint for a couple of years in the pharmaceutical industry to learn about drug development and then go back to clinical practice," he recalled. But that stint turned into more than a decade, and counting.
"I also began thinking about unmet needs and found myself asking ‘what else is there to be solved?’ " he contended.
Nkulikiyinka had helped bring two new therapies for cardiovascular/metabolic conditions through clinical trials to regulatory approvals worldwide. And then his direction began to change again. "I started thinking about getting on the entrepreneurship train," he asserted. "So, when David knocked on my door, it was exactly at the right time."
They co-founded GenKardia in 2023, with Zebrowski as CEO and Nkulikiyinka as Chief Development Officer.
Building Momentum Toward Heart Failure Clinical Trials
Winning an XSeed Award would enable Nkulikiyinka and Zebrowski to assess the ability of GKA-100 to affect protein levels in cultures of human cardiomyocytes. With that validation, they could then test GKA-100 in engineered heart tissue, a model to observe the mechanics of cardiac contractility and relaxation.
Following those studies, they would move the drug candidate in a mouse model of heart failure, and then raise the capital to support an Investigational New Drug (IND) submission with the FDA.
"It has taken a lot of collaboration with stakeholders externally — in academia, regulatory agencies and other people in the industry — and then internally as well to really get the needle moving," Nkulikiyinka said. Five years from now, he hopes they will have a drug in clinical trials.
Nkulikiyinka’s Lessons for New Entrepreneurs
Although he still considers himself a "newbie" in the startup world, Nkulikiyinka does have advice to share with other academics looking to cross the bridge into entrepreneurship.
"Trust the generosity of people in this industry. They are very generous with their time, their insights and their advice," he encouraged. "Don't hesitate to reach out to people. Look at your network. See who knows someone. At the very least, it leads to a nice conversation."
Being flexible is also important. "Be willing to try different things. Get out of your comfort zone every single day, because the number of topics you have to think about is just enormous," Nkulikiyinka added. "Once you go to the entrepreneurship side, you have to cover all the bases and be willing to put in the time to read and inform yourself."
He also acknowledged that entrepreneurship is not for the faint of heart.
"Know your limits. You have to deal with a lot of uncertainty. Is your personality a match for that kind of work?" he queried. "Are you able to deal with the fact that you won't know if you're going to succeed or not? Reflect about that before you embark on this journey."
It's a journey that has brought Nkulikiyinka great satisfaction and tremendous rewards.
"Thinking how this could change the world and waking up every day knowing that is a possibility is very rewarding," he concluded. "It's even more rewarding when you're at the beginning of the journey and it's down to you to make it happen. It's a great feeling to know that you may get something to the market that will help so many people."
Learn more about the XSeed Award and past winners.