Recent advancements in gene therapy have shown promising results in reversing heart failure and restoring cardiac functionality in a large animal model. This groundbreaking therapy enhances the heart’s pumping capacity and significantly boosts survival rates, with researchers highlighting “an unprecedented recovery of cardiac function.”
At present, heart failure is considered irreversible. Without a transplant, most treatment options focus on alleviating heart stress and slowing the progression of this often-fatal condition. However, if this gene therapy demonstrates comparable efficacy in upcoming clinical trials, it has the potential to heal the hearts of the 1 in 4 individuals who will develop heart failure in their lifetime.
A “night and day” change
The research team concentrated on enhancing a vital heart protein known as cardiac bridging integrator 1 (cBIN1). They identified that heart failure patients have reduced levels of cBIN1 – the lower the level, the higher the risk of severe illness. “When cBIN1 levels drop, we know patients won’t fare well,” says Robin Shaw, MD, PhD, director of the Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI) at the University of Utah and a co-senior author of the study. “It’s straightforward to ask, ‘What happens if we restore it?'”
To elevate cBIN1 levels in heart failure cases, scientists employed a benign virus commonly used in gene therapy to introduce an additional copy of the cBIN1 gene into heart cells. They administered the virus via injection into the bloodstream of pigs diagnosed with heart failure. The virus traveled through the bloodstream to the heart, delivering the cBIN1 gene directly to heart cells.
In this heart failure model, the prognosis is generally grim, with typical outcomes leading to death within months. Remarkably, all four pigs treated with the gene therapy survived for six months, the duration set for the study.
Crucially, the treatment did more than halt the progression of heart failure; it led to actual improvements in key heart function metrics, hinting at the heart’s ability to repair itself.
Shaw notes that witnessing such a reversal of existing heart damage is extremely rare. “We’ve never encountered such efficacy in heart failure research,” he states. Prior heart failure treatments have achieved only 5-10% improvements in cardiac function, whereas the cBIN1 gene therapy resulted in a 30% enhancement. “It’s a remarkable difference,” adds Shaw.
The efficiency of treated hearts in pumping blood, a primary indicator of heart failure severity, increased over time – not fully back to healthy levels, but closer to those of normal hearts. The hearts also maintained a less dilated and thinner structure, resembling non-failing hearts more closely. Throughout the trial, even as the gene-treated pigs faced similar cardiovascular stress that initially caused their heart failure, the therapy restored their blood pumped per heartbeat to normal levels.
“Despite the ongoing stress faced by the heart, the treated animals showcased recovery in heart function, and the heart exhibited stabilization or reduced size,” explains TingTing Hong, MD, PhD, associate professor of pharmacology and toxicology and CVRTI investigator at the University of Utah and co-senior author of the study. “We refer to this as reverse remodeling, indicating a return to the appearance of a healthy heart.”
A vital element of heart function
The researchers believe that cBIN1’s capacity to improve heart function stems from its role as a scaffold that interacts with key proteins critical to heart muscle function. “cBIN1 acts as a central signaling hub that manages various downstream proteins,” explains Jing Li, PhD, associate instructor at CVRTI. By organizing other components of heart cells, cBIN1 aids in restoring essential heart cell functions. “cBIN1 provides benefits across multiple signaling pathways,” adds Li.
Indeed, the gene therapy appeared to enhance heart function at a microscopic level, leading to better-structured heart cells and proteins. The researchers are hopeful that cBIN1’s role as a master regulator of heart cell architecture could contribute to the success of cBIN1 gene therapy and potentially change the landscape of heart failure treatment by directly targeting heart muscle.
In collaboration with industry partner TikkunLev Therapeutics, the research team is currently modifying the gene therapy for human application, with plans to seek FDA approval for clinical trials by fall 2025. Although the researchers are enthusiastic about the results thus far, the therapy must undergo toxicology testing and adhere to other safety protocols. Also, like many gene therapies, its potential effectiveness for individuals with natural immunity to the delivery virus remains uncertain.
However, the team remains optimistic. “When you observe results in large animals that closely align with human physiology, it prompts deeper consideration,” Hong states. “Considering this human condition impacts over six million Americans, there’s a possibility we could find a cure.”
