Work described in this story was made possible in part by federal funding supported by taxpayers. At Harvard Medical School, the future of efforts like this - done in service to humanity - now hangs in the balance due to the government's decision to terminate large numbers of federally funded grants and contracts across Harvard University.
- By SUZANNE DAY and STEPHANIE DUTCHEN
People with hypertrophic cardiomyopathy (HCM) - often an inherited disease marked by abnormally thickened heart muscle - face a looming risk of heart failure, arrhythmia, and sudden cardiac arrest. Many experience no signs and don't realize they have the condition, while others suffer progressively worse symptoms such as chest pain, shortness of breath, and palpitations. HCM can make exercise unsafe and is the leading cause of sudden cardiac death among young athletes, though such events are rare.
For many years, scientists had little understanding of what caused HCM, and treatment options - such as beta blockers, calcium channel blockers, and surgery to thin the heart muscle - didn't stop disease progression, and too often left patients needing heart transplantation.
Then, starting with a landmark publication in Cell in 1990, Harvard Medical School researchers uncovered critical insights into the genetic and molecular underpinnings of the disease. Their federally supported research paved the way for the first FDA-approved precision treatment for HCM: mavacamten (Camzyos).
Sparking insight into HCM
The challenge of unraveling the basic biology of HCM ignited the passion of two scientists who have dedicated their careers to cardiovascular and genetic research.
Christine (Kricket) Seidman, the HMS Thomas W. Smith Professor of Medicine at Brigham and Women's Hospital and professor of genetics in the Blavatnik Institute at HMS, and her husband Jonathan Seidman, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics at HMS, share both a laboratory and a drive to translate scientific knowledge into better outcomes for patients.
The 1990 discovery and those that followed arose in part because Kricket, a practicing cardiologist, brought her experiences seeing patients in the clinic back to the laboratory and worked closely with geneticist Jonathan to determine what was causing HCM and whether something could be done to alleviate it.
"He'll see a problem differently than I do, and when we work together, we see new opportunities we wouldn't have found alone," Kricket said.
Members of the Seidman Lab discovered that HCM is caused by mutations in the genes encoding the heart's sarcomere, the structure responsible for muscle contraction. They found that these mutations increase the heart muscle's contractility while impairing its ability to relax, slowly exhausting the muscle and increasing the risk of arrhythmias such as atrial fibrillation.
The team's work made genetic diagnosis of HCM possible and illuminated a path toward intervening in the disease process.
A leap into industry
Understanding the mechanism was one hurdle. Finding a way to slow, stop, or reverse it was quite another.
As Jonathan recalled, moving from fundamental discoveries to a treatment required a leap from the lab into the biotechnology industry, where they could apply larger-scale screening and development.
"In academic settings, we can set up prototype experiments and test a few simple, straightforward questions," Kricket explained. "But if you want to make a molecule that you ultimately give to patients, you have to test thousands."
The Seidmans made that leap by cofounding a biotechnology company, MyoKardia, that set out to target the heart's sarcomere - specifically, the contractile protein myosin - with small-molecule drugs.
Robert McDowell, then serving as the company's chief scientific officer, led a team of scientists who used high-throughput screening to identify the compound that would become mavacamten - the first cardiac myosin inhibitor brought into clinical trials.
The central challenge was to reduce cardiac myosin activity enough to restore healthy relaxation between heartbeats without compromising the organ's ability to pump blood. The trials confirmed that mavacamten was safe and effective in normalizing the heart's contraction-relaxation cycle in participants with the more common type of HCM, called obstructive HCM.
"We had physicians calling us and saying, 'Our patients were barely able to use a wheelchair, and now they are running on the beach,'" McDowell said. "I still get goosebumps even thinking about that."
Expanding treatment options, improving lives
Bristol Myers Squibb acquired MyoKardia in 2020. It led mavacamten's later-stage clinical development and its approval by the FDA in 2022. Now known as Camzyos, mavacamten has improved many patients' ability to exercise, relieved certain symptoms, and reduced the need for surgery. The team hopes it also lowers the disease's serious long-term risks.
"Patients have more energy to do the things they want, and they have less fear because they feel their heart is functioning better," said Kricket. "We hope treatment will mean that they won't develop heart failure, but that remains to be seen."
The Seidmans' work paved the way for others to explore treatments for HCM and related conditions. Separate teams are spearheading development of additional drugs that target cardiac myosin or other aspects of the sarcomere.
"Mavacamten has allowed us to see that it's possible to change the sarcomere to become more powerful or less powerful, and it supports the idea that it's worth trying to target difficult, complex structures like it," said Kricket. "Having 'competing' drug candidates from other companies is great because each new medicine offers an opportunity for improvement."
While they are thrilled to witness the fruition of their research contributions, Kricket and Jonathan are already delving deeper into disease mechanisms and working to help more patients. For instance, only a subset of HCM patients qualify for mavacamten. The Seidmans are also committed with colleagues' optimism to advance the potential of gene therapies and RNAi technologies to cure HCM by addressing the underlying mutations.
"It feels absolutely wonderful to have been part of a group of fabulous and brilliant scientists, to understand what's broken and find a way to minimize the damage, and to continue to work to fix it, bringing hope to lots of patients for lots of diseases," said Kricket.
Bristol Myers Squibb was not involved in the production of this video or news article.
