Gene Therapy Reverses Effects of Heart Failure and Restores Heart Function in Minipigs

Researchers at the Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, and the University of Utah School of Medicine, have demonstrated that a gene therapy can reverse the effects of heart failure (HF) and restore heart function in a large animal model. Their study showed that the adeno-associated virus 9 (AAV9)-packaged cardiac bridging integrator 1 (cBIN1) gene therapy increased the amount of blood the heart can pump and dramatically improved survival in minipigs with non-ischemic heart failure with reduced ejection fraction (HFrEF).

Research co-lead Robin Shaw, MD, PhD, director of the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) at the University of Utah said that the kind of reversal of existing damage observed in the study was highly unusual. “In the history of heart failure research, we have not seen efficacy like this.” Previous attempted therapies for heart failure have shown improvements in heart function on the order of 5–10%. cBIN1 gene therapy improved function by 30%. “It’s night and day,” Shaw added.

The results of the preclinical study are reported by co-senior author Shaw, and colleagues, in npj Regenerative Medicine. In their paper, titled “Cardiac bridging integrator 1 gene therapy rescues chronic non-ischemic heart failure in minipigs,” the researchers concluded, “The success of cBIN1 gene therapy in swine with non-ischemic HFrEF can be a gateway to future clinical trials testing its efficacy in patients with HFrEF.”

The team suggests that an application to the FDA for approval to carry out a human clinical trial may be made within the next 12 months.

Currently, heart failure is irreversible. “Heart failure (HF), a clinical syndrome resulting from structural and functional impairment of cardiac filling and/or ejection of blood, has become a global public health burden affecting more than 64 million people worldwide,” the authors wrote. In the absence of a heart transplant, most medical treatments aim to reduce the stress on the heart and slow disease progression. “Despite the high mortality and morbidity caused by HF, the mainstream therapeutic options for HF patients are still mainly limited to lifestyle management, systemic neurohormonal interventions, and mechanical assisted device or heart transplant,” the investigators added.

In recent years, gene therapy has emerged as an approach to deliver or modify target genes directly benefiting failing heart muscle. For their study, the researchers focused on restoring the critical heart protein cardiac bridging integrator 1 (cBIN1), a cardiomyocyte membrane scaffolding protein. They knew that the level of cBIN1 was lower in heart failure patients, and that the lower it was, the greater the risk of severe disease. “Previous studies indicate that cardiomyocyte transcription and protein expression of BIN1 are reduced in animal and human hearts with HF,” they wrote.

For their newly reported study, the team quantified myocardial cBIN1 protein levels in heart tissue samples obtained from hFrEF patients. “… we report that in human patients with HF with reduced ejection fraction (HFrEF), left ventricular cBIN1 levels linearly correlate with organ-level ventricular remodeling such as diastolic diameter.” As Shaw further commented, “When cBIN1 is down, we know patients are not going to do well. 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 used an AAV9 vector to deliver an extra copy of the cBIN1 gene to heart cells in a minipig model of right ventricular tachypacing-induced non-ischemic dilated cardiomyopathy (DCM) and chronic HFrEF. The team injected the gene therapy into the bloodstream of the pigs, and it was transported to the heart, where the cBIN1 gene was delivered into heart cells.

The heart failure model investigated generally leads to death within a few months. However, the investigators found that all four pigs that received the gene therapy in their heart cells survived for six months, the endpoint of the study. Importantly, the treatment didn’t just prevent heart failure from worsening. Some key measures of heart function improved, suggesting the damaged heart was repairing itself.

“Using a minipig model of right ventricular tachypacing-induced non-ischemic dilated cardiomyopathy and chronic HFrEF, we identified that a single intravenous low dose (6 x 10¹¹ vg/kg) of adeno-associated virus 9 (AAV9)-packaged cBIN1 improves ventricular remodeling and performance, reduces pulmonary and systemic fluid retention, and increases survival in HFrEF minipigs,” the authors stated.

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.

Although throughout the trial the gene-transferred animals experienced the same level of cardiovascular stress that had led to their heart failure, the administered gene therapy restored the amount of blood pumped per heartbeat back to entirely normal levels. The treatment in addition seemed to improve heart function on the microscopic level, with better-organized heart cells and proteins.

“In this study, we report in swine the efficacy of an AAV9-based gene therapy replenishing cBIN1 to recover the subcellular architecture of failing cardiomyocytes for functional rescue of non-ischemic DCM and HFrEF,” the team wrote. “These data provide strong evidence in support of the therapeutic efficacy of AAV9-cBIN1 in large mammals with HFrEF. Moreover, the strength of LV free wall myocardial cBIN1 in correlating with LV remodeling and dysfunction in human patients with HFrEF … further supports the promising potential to translate cBIN1 gene therapy to humans.”

“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 stabilizes or shrinks,” commented co-senior author TingTing Hong, MD, PhD, associate professor of pharmacology and toxicology and CVRTI investigator at the University of Utah. “We call this reverse remodeling. 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. “cBIN1 serves as a centralized signaling hub, which actually regulates multiple downstream proteins,” explained Jing Li, PhD, associate instructor at CVRTI. By organizing the rest of the heart cell, cBIN1 helps restore critical functions of heart cells. “cBIN1 is bringing benefits to multiple signaling pathways,” Li added.

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 a human clinical trial in the fall of 2025. While the researchers are excited about the results so far, the therapy still has to pass toxicology testing and other safeguards. It also 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 says. “This human disease, which affects more than six million Americans—maybe this is something we can cure.”

As the researchers concluded in their paper, their study findings offer up “strong preclinical evidence in support of the promise of AAV9-cBIN1 as a therapy for patients with HFrEF not just to limit the deterioration of failing heart muscle but reverse failing heart muscle, restoring cardiac function.”