University of Pittsburgh researchers have developed an adeno-associated virus (AAV) vector-based approach to increase protein kinase G1 (PKG1) signaling, specifically in cardiomyocytes. Using a cardiac troponin T (cTnT) promoter which directs cardiomyocyte-specific gene expression, vectors encoding the sequence for human mycPKG1⍺ have been produced (AAV-cTNT-mycPKG1). Encoding for PKG1 has been shown to increase cardiac function and could provide a novel treatment strategy for heart failure patients.
Description
Nearly 6.5 million Americans over the age of 20 years live with some form of heart failure which directly accounts for 8.5% of all heart disease deaths and contributes to 36% of cardiovascular disease deaths. Given its social impact on patient quality of life and economic impacts as the top cause of hospitalizations in Medicare patients, there remains a great need to develop safe and effective therapies to match this growing need. Deficiency of key cardiac natriuretic peptides is linked to many cardiovascular diseases, and understanding this process and the downstream effects led to the discovery of the role of a cGMP-dependent protein kinase, PKG1 in heart failure. This AAV-vector could overcome the deficiencies of these cardiac natriuretic peptides and provide a novel approach to treatment of cardiomyopathy.
Applications
• Heart failure
• Cardiac hypertrophy
• Cardiac arrhythmias
Advantages
Current treatments for cardiovascular diseases include small molecules for neprilysin inhibition and soluble guanylyl cyclase activators. However, systemic administration and an increased risk of off-target interactions lead to side effects.
AAVs are increasingly used to deliver encoding for gene expression to cells. The inclusion of the cTnT promotor led to cell specific targeting of cardiomyocytes and should reduce the risk of off-target side effects compared to systemic approaches.
Invention Readiness
Previous work identified the role of PKG1 in the pathways by which cardiac natriuretic peptides (CNP) regulate cardiovascular physiology. Human iPS cell derived cardiomyocytes were transduced using AAV6-cTnT-mycPKG1 leading to an amplification of CNP-induced SERCA2a SUMOylation, a known pathway in maintaining the cardiac cycle. In vivo studies found mice injected with AAV9-cTnT-mycPKG1WT viruses led to selective expression of PKG1 in cardiomyocytes confirming the cell specific nature of this approach. In a murine non-ischemic dilated cardiomyopathy model, injection of AAV9-cTnT-mycPKG1WT improved left ventricular function. Further studies are required to explore the potential of this approach in humans.
IP Status
Patent pending
