Gene therapy reverses heart failure in large animal model


Friday, 13 December, 2024


Gene therapy reverses heart failure in large animal model

A new gene therapy has been found to reverse the effects of heart failure and restore heart function in a large animal model. Developed at The University of Utah and described in npj Regenerative Medicine, the therapy increases the amount of blood the heart can pump and dramatically improves survival, in what has been described as an unprecedented recovery of cardiac function.

Currently, heart failure is irreversible. In the absence of a heart transplant, most medical treatments aim to reduce the stress on the heart and slow the progression of the often-deadly disease. The Utah researchers were instead focused on restoring levels of a critical heart protein called cardiac bridging integrator 1 (cBIN1), which is lower in heart failure patients — and the lower it is, the greater the risk of severe disease.

“When cBIN1 is down, we know patients are not going to do well,” said Dr Robin Shaw, Director of Utah’s Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) and a co-senior author on the new study. “It doesn’t take a rocket scientist to say, ‘What happens when we give it back?’”

To try and increase cBIN1 levels in cases of heart failure, the 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 into the heart, where it delivered the cBIN1 gene into heart cells.

For this heart failure model, heart failure generally leads to death within a few months. But all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study. Furthermore, the treatment didn’t just prevent heart failure from worsening; some key measures of heart function actually improved, suggesting the damaged heart was repairing itself. According to Shaw, this kind of reversal of existing damage is highly unusual.

“In the history of heart failure research, we have not seen efficacy like this,” he said. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5–10%, but cBIN1 gene therapy improved function by 30%. “It’s night and day,” Shaw said.

Microscope images of failing heart cells (top) and heart cells that received gene therapy (bottom). Cell boundaries, labelled in magenta, are more organised after gene therapy, and the level of cBIN1 protein (green) is higher. Image credit: Hong Lab.

The treated hearts’ efficiency at pumping blood, which is the main measure of the severity of heart failure, increased over time — not to fully healthy levels, but to close that of healthy hearts. The hearts also stayed less dilated and less thinned out, closer in appearance to that of non-failing hearts. Furthermore, despite the fact that the gene-transferred animals experienced the same level of cardiovascular stress that had led to their heart failure, the treatment restored the amount of blood pumped per heartbeat back to entirely normal levels.

“Even though the animals are still facing stress on the heart to induce heart failure, in animals that got the treatment, we saw recovery of heart function and that the heart also stabilises or shrinks,” said Associate Professor TingTing Hong, co-senior author on the study. “We call this reverse remodelling. It’s going back to what the normal heart should look like.”

The researchers think that cBIN1’s ability to rescue heart function hinges on its position as a scaffold that interacts with many of the other proteins important to the function of heart muscle. So, by organising the rest of the heart cell, cBIN1 helps to restore critical functions.

“cBIN1 serves as a centralised signalling hub, which actually regulates multiple downstream proteins,” explained Dr Jing Li, associate instructor at CVRTI and first author on the study.

Indeed, the gene therapy seemed to improve heart function on the microscopic level, with better-organised heart cells and proteins. The researchers hope that cBIN1’s role as a master regulator of heart cell architecture could help cBIN1 gene therapy succeed and introduce a new paradigm of heart failure treatment that targets heart muscle itself.

Along 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 trial in 2025. Of course, the therapy still has to pass toxicology testing and other safeguards, and it remains to be seen if it will work for people who have picked up a natural immunity to the virus that carries the therapy. But the researchers are optimistic.

“When you see large animal data that’s really close to human physiology, it makes you think,” Hong said. “This human disease, which affects more than six million Americans, maybe this is something we can cure.”

Top image credit: iStock.com/VectorFusionArt

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