Heart failure is a major clinical problem which is becoming worse as the Australian population ages, and rates of obesity and diabetes increase. Although current heart failure therapies have provided benefit, and survival after diagnosis has improved, the disease process typically continues, and the death rate remains high; 50% of patients with severe heart failure will die within one year.
Our research program focuses on developing new gene therapy approaches based on the known protective properties of phosphoinositide-3 kinase (PI3K) in the heart, while limiting any side effects in other tissues. Our previous work has shown that PI3K gene therapy provides benefit in heart disease mouse models (pressure overload-induced pathological cardiac hypertrophy [Weeks et al. Circulation-Heart Failure 2012; 5: 523-34] and diabetic cardiomyopathy [Prakoso et al. Clinical Science 2017; 131:1345-60]. We are developing and evaluating adeno-associated viral vectors (AAVs) incorporating a constitutively active form of PI3K with the goals of: 1) increasing cardiac-specificity, 2) enhancing the design for mass AAV production, and 3) translation in a large animal model of heart failure. Initial development and testing will be performed in mice, with the most optimal AAVs tested in sheep.
The immediate outcome of this research will be the development and optimisation of PI3K based-gene therapies, and assessment in small and large animal models of heart failure. The long-term outcome could be the entry of these therapies into clinical trials for patients with heart failure.