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 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.

Robin Shaw, MD, PhD, (left) and TingTing Hong, MD, PhD, (right) at the lab bench. [Charlie Ehlert/University of Utah Health]
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?’”
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.

Jing Li, PhD, first author on the paper. [Thuy Ha]
“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.
“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.”

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.

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.”
https://www.genengnews.com/topics/translational-medicine/gene-therapy-reverses-effects-of-heart-failure-and-restores-heart-function-in-minipigs/

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