A new gene therapy can reverse the effects of heart failure and restore cardiac function in a large animal model. The therapy increases the amount of blood the heart can pump and dramatically improves survival, in what a paper describing the results calls “an unprecedented recovery of cardiac function.”
Currently, heart failure is irreversible. In the absence of a heart transplant, most medical treatments aim to reduce stress on the heart and slow the progression of this often fatal disease. But if gene therapy shows similar results in future clinical trials, it could help cure the hearts of the 1 in 4 people alive today who will eventually develop heart failure.
A change of “day and night”
The researchers focused on restoring a critical cardiac protein called cardiac bridging integrator 1 (cBIN1). They knew that the level of cBIN1 was lower in patients with heart failure and that the lower it was, the greater the risk of severe disease. “When cBIN1 is low, we know patients will not do well,” says Robin Shaw, MD, PhD, director of the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) at the University of Utah and co-senior author. in the studio. “It doesn’t take a genius to say, ‘What will happen when we give it back?'”
To try to increase cBIN1 levels in heart failure, scientists turned to a harmless virus commonly used in gene therapy to deliver an extra copy of the cBIN1 gene to heart cells. They injected the virus into the bloodstream of pigs with heart failure. The virus moved through the bloodstream to the heart, where it introduced the cBIN1 gene into heart cells.
For this heart failure model, heart failure usually causes death within a few months. But the four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study.
Importantly, the treatment not only prevented heart failure from worsening. Some key measures of heart function actually improved, suggesting that the damaged heart was repairing itself.
Shaw emphasizes that this type of reversal of existing damage is very unusual. “In the history of heart failure research, we haven’t seen efficacy like this,” Shaw says. Previous attempts at therapies for heart failure have shown improvements in cardiac function on the order of 5 to 10%. cBIN1 gene therapy improved function by 30%. “It’s night and day,” Shaw adds.
The efficiency of the treated hearts in pumping blood, which is the main measure of the severity of heart failure, increased over time, not to completely healthy levels, but close to those of healthy hearts. The hearts also remained less dilated and less thinned, appearing closer to that of non-failing hearts. Although, throughout the trial, the animals to which the gene had been transferred experienced the same level of cardiovascular stress that had caused heart failure, the treatment restored the amount of blood pumped per heartbeat to completely normal levels. .
“Although the animals still face stress on the heart to induce heart failure, in the animals that received the treatment, we saw a recovery of heart function and the heart also stabilized or shrank,” says TingTing Hong, MD, PhD, associate professor. of pharmacology and toxicology and CVRTI researcher at the U and lead co-author of the study. “We call this reverse remodeling. It’s getting back to what a normal heart should look like.”
A cornerstone of the heart
The researchers believe that cBIN1’s ability to rescue cardiac function depends on its position as a scaffold that interacts with many of the other proteins important for cardiac muscle function. “cBIN1 serves as a centralized signaling hub, which actually regulates multiple downstream proteins,” says Jing Li, PhD, associate instructor at CVRTI. By organizing the rest of the heart cells, cBIN1 helps restore critical heart cell functions. “cBIN1 provides benefits to multiple signaling pathways,” adds Li.
In fact, gene therapy appeared to improve heart function at the microscopic level, with heart cells and proteins better organized. The researchers hope that cBIN1’s role as a master regulator of cardiac cell architecture can help cBIN1 gene therapy be successful and introduce a new heart failure treatment paradigm targeting the heart muscle itself.
Together with industry partner TikkunLev Therapeutics, the team is currently adapting the gene therapy for use in humans and intends to apply for FDA approval for human clinical trials in the fall of 2025. While researchers are Enthusiastic with the results so far, the therapy still has to pass toxicological tests and other safeguards. And, like many gene therapies, it remains to be seen whether it will work for people who have acquired natural immunity to the virus carried by the therapy.
But researchers are optimistic. “When you see big data from animals that are very close to human physiology, it makes you think,” Hong says. “This human disease, which affects more than six million Americans, may be something we can cure.”