‘PLOS ONE’ publishes results of cardiac-directed catalytically inactive AC6 in mice after sustained β-adrenergic stimulation
August 2, 2017
Study shows AC6 mutant gene protects the heart from deleterious effects of sustained β-adrenergic stimulation as frequently seen in clinical heart failure
San Diego, CA – Renova™ Therapeutics, a biotechnology company developing gene and peptide-based treatments for cardiovascular and metabolic diseases, today announced publication in PLOS ONE of results of cardiac-directed expression of a mutant form of adenylyl cyclase type 6 (AC6mut). Unlike AC6, AC6mut does not produce cyclic AMP (adenosine monophosphate; cAMP) – and previous research suggests the beneficial effects of AC6 do not depend on cAMP generation. This latest data indicate that AC6mut protects the heart from sustained β-adrenergic receptor stimulation, a common occurrence in heart failure patients.
The study was conducted by Dr. H. Kirk Hammond and his colleagues at the University of California – San Diego and the Veterans Affairs San Diego Healthcare System. Dr. Hammond is a co-founder of Renova Therapeutics.
In the study, AC6mut mice received osmotic mini-pumps to provide continuous isoproterenol infusion for seven days. Isoproterenol infusion caused deleterious cardiovascular effects that were attenuated by AC6mut. When compared to transgene controls, AC6mut mice showed superior left ventricular (LV) function, manifested by higher values for LV ejection fraction (p=0.047), LV peak +dP/dt (p=0.03), LV peak -dP/dt (p=0.008), end-systolic pressure-volume relationship (p=0.003) and cardiac output (p<0.03).
LV samples of AC6mut mice had more sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a) protein (p<0.01), which likely contributed to improved systolic and diastolic LV function. AC6mut mice also had lower rates of cardiac myocyte apoptosis (p=0.016), reduced caspase 3/7 activity (p=0.012) and increased B-cell lymphoma 2 expression (p=0.0001).
Dr. Hammond and colleagues are exploring the use of AC6mut as a potential next-generation product following AC6 gene transfer for the treatment of heart failure. AC6 is a protein that influences heart function and is reduced in function or amount in failing hearts. A randomized Phase 2 clinical trial showed that AC6 gene transfer safely increased heart function beyond optimal therapy in patients with heart failure and reduced ejection fraction (JAMA Cardiology). AC6 gene transfer is being developed by Renova Therapeutics as RT-100, its lead gene therapy candidate advancing to a Phase 3 study known as FLOURISH.
About heart failure
Heart failure is a chronic disease characterized by the inability of the heart to pump sufficient blood to meet the body’s demands. It is a progressive and fatal chronic condition, and symptoms worsen over time. Heart failure afflicts more than 28 million people globally and is the only cardiovascular disease that is increasing in prevalence. In the United States, it is the most common cause for emergency hospital admissions in patients 65 and older.
- Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics–2013 update: a report from the American Heart Association. Circulation. 2013;127:e6–e245.
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