Fight Aging!

Progressive heart failure is at presently largely irreversible, though there is suggestive evidence for senolytic therapies to clear senescent cells from cardiac tissue to be capable of reversing at least some of its aspects, such as ventricular hypertrophy, the enlargement and weakening of heart muscle. Heart failure can arise from a combination of several underlying causes leading to some combination of structural alteration of the heart or loss of function independently of altered structure, and so there are many different classifications of heart failure based on specific outcomes.

One of the possible approaches to the treatment of age-related disease is to compensate for a specific failure, rather than trying to address its root causes. Sometimes this can be worth the effort. For example, present treatments that control blood pressure in no way address the root causes of age-related hypertension, but produce a fair-sized reduction in mortality because the raised blood pressure of hypertension is very damaging in and of itself.

In today's open access paper, researchers use a gene therapy approach to compensate for a maladaptive reduction in the expression of a gene involved in regulating heart tissue structure and function. This change in expression that occurs in the environment of heart failure is not a root cause of heart failure, just as hypertension is nowhere near the root causes of aging. It is sufficiently problematic in and of itself, however, that a compensatory therapy may be able to produce enough benefit to be worth the effort.

New Gene Therapy Reverses Heart Failure in Large Animal Model

A new gene therapy can reverse the effects of heart failure and restore heart function in a large animal model. The researchers were focused on restoring a critical heart protein called cardiac bridging integrator 1 (cBIN1). 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. 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. Importantly, 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. Previous attempted therapies for heart failure have shown improvements to heart function on the order of 5-10%. cBIN1 gene therapy improved function by 30%.

Cardiac bridging integrator 1 gene therapy rescues chronic non-ischemic heart failure in minipigs

Heart failure (HF) is a major cause of mortality and morbidity worldwide, yet with limited therapeutic options. Cardiac bridging integrator 1 (cBIN1), a cardiomyocyte transverse-tubule (t-tubule) scaffolding protein which organizes the calcium handling machinery, is transcriptionally reduced in HF and can be recovered for functional rescue in mice. Here 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.

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 × 10^11 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. In cardiomyocytes, AAV9-cBIN1 restores t-tubule organization and ultrastructure in failing cardiomyocytes. In conclusion, AAV9-based cBIN1 gene therapy rescues non-ischemic HFrEF with reduced mortality in minipigs.