heart illustration with syringe connected to blood vessel
The Future of Cardiology

Musunuru Seeks the Holy Grail: A Cure for the World’s Number One Killer

By Catharine Restrepo L’93

met Kiran Musunuru, ML’19 when he was a student in Penn Law’s Master in Law program, a Penn Law degree launched in 2014 for non-lawyers, providing targeted legal education to industry leaders and accomplished academics, professionals and Penn students to enrich their important work by studying the law impacting their fields and enabling innovation. Musunuru’s timing was excellent, coinciding with his efforts to launch and raise capital for Verve Therapeutics, which is developing a vaccine for heart disease.

Cardiovascular disease leads the world in death and misery. Eighteen million lives lost each year and immense suffering for those living with this insidious disease, make it a true pandemic, the greatest global public health crisis of the twenty-first century, exceeding by multiples cancer (9 million deaths annually) and COVID-19 (2.5 million deaths in the first year). It is an indiscriminate killer, knowing no gender, racial, geographic, or socioeconomic boundaries. Worse still, it is rising again, ready to explode, Musunuru believes, with increased obesity, diabetes, pollution, and tobacco use abruptly reversing what had been a positive trend.

One-third of those who suffer heart attacks do not receive help in time and die. For the survivors, quality of life is diminished, requiring interventions or expensive medication, all with attendant challenges. Scientific advances help, but never make the victim whole again after suffering a heart attack. Lack of adherence to prescribed medication leads to future heart attacks. Inequity prevails as access and costs widen the gap in health outcomes between rich and poor.

Musunuru, a Penn cardiologist, geneticist and professor of medicine at the Perelman School of Medicine, dreamed of eradicating this killer by preventing it from happening in the first place. Thanks to breakthroughs in modern biomedicine — human genetic analysis and gene editing — harnessed by Verve Therapeutics, a company Musunuru founded with a team of world-renowned researchers in cardiovascular genetics and gene editing, this is no longer a dream, it is moving towards reality. Musunuru and Verve are creating a vaccine — a permanent preventative treatment for cardiovascular disease delivered with just one shot. Phase 1 clinical trials are planned for next year.

Musunuru says “sometimes it’s better to be lucky than good” when describing how he came to this moment. Humility is one of Musunuru’s most endearing qualities.

Musunuru described several key factors leading to this monumental breakthrough: finding a decades-old unresolved study of a family now labeled ‘genetic superheroes,’ genome sequencing, CRISPR gene editing and lipid nanoparticles (LNPs) encapsulating RNA (the same novel technology used in some COVID-19 vaccines).

Sifting through unresolved cases, Musunuru and team found a study of four siblings with abnormally low levels of cholesterol and triglycerides and a complete absence of cardiovascular disease. Long after the study had been shelved, the siblings were alive and well, the original researchers and lab remained in place, and even the DNA samples had been meticulously preserved, providing valuable data despite the passage of time.

Using genome sequencing and data processing speeds unavailable in the original study, Musunuru was able to identify the precise genetic mutations the siblings shared which effectively turned off the gene responsible for releasing cholesterol and triglycerides into the body which result in plaque buildup and heart disease. With this gene turned off, the siblings enjoy unusually low levels of cholesterol and triglycerides and perfect cardiac health. These ‘genetic superheroes’ have naturally occurring genetic variants that protect them from heart disease and stroke.

Musunuru described the moment of this discovery as being hit by a thunderbolt. “Rarely in science is the answer so clear but in this case it was,” he said. With the genetic variants so clearly identified, Musunuru knew if they could replicate the variants’ effects in the rest of us, we could be like these genetic superheroes, and enjoy the same protection from cardiac disease.

That magical moment was in 2010.

Musunuru and team ramped up their efforts, harnessing advances in gene editing and gene mapping technology, along with all they were learning from additional studies and more genetic superheroes, plus advances in ways to deliver therapies into cells — coincidentally, using the same LNP technology as the first two US-approved COVID-19 vaccines.

Fast forward to 2018, during which they believed they found a way.

That year, armed with this amassed knowledge and $58.5 million in capital to start, Musunuru and his team of cardiovascular, human genetics and gene editing experts launched Verve, with the lofty goal to eradicate cardiovascular disease the world over with a one-and-done treatment.

They began promising studies on non-human primates (monkeys) in 2019.

Musunuru described Thanksgiving 2019 as starting like any other, visiting and chatting with family. While pretending to briefly check his email, in fact, he was surreptitiously checking the latest data from an early primate study.

He had been hoping to find even slight editing of the primate’s genes, say two to ten percent. When he saw they had achieved as much as 60 to 70 percent editing of the subjects’ genes, with a corresponding drastic reduction in cholesterol, he couldn’t believe his eyes or hide his elation.

Much like before, he described feeling as if hit by a thunderbolt. This was monumental. With this permanent edit of the subjects’ genes, they had effectively inoculated them from cardiovascular disease.

Ecstatic and euphoric, he could no longer pretend to engage in the family chatter. He immediately started calling the members of his team despite the holiday.

In May, in the scientific journal Nature, Musunuru and Verve reported that in subsequent primate studies, the subjects remained healthy and their deep cholesterol reductions were stable eight months after treatment with no negative side effects. (In June, Verve went public with an IPO that increased the company’s net worth to $2 billion.)

Next year, Verve hopes to test their treatment in Phase 1 clinical trials with some of the sickest patients whose lives have been devastated by cardiovascular disease.

Perhaps within the following 5 to 10 years comes the next part of the plan: giving the treatment to heart attack victims as part of their routine care.

Finally, if all goes well with the trials, this treatment could eventually be available on a global scale, as part of routine vaccinations before the first sign of heart disease. One shot to prevent cardiovascular disease, ending this source of misery and literally tapping into a fountain of youth.

That would be a dream come true for Musunuru and millions of patients.

Catharine Restrepo is the Executive Director of the Master in Law Program at the University of Pennsylvania Carey Law School.