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Novel gene therapy approach for cardiovascular diseases

Prof. Christian Kupatt, MRI, Technische Universität München; Prof. Rabea Hinkel, Deutsches Primatenzentrum (DPZ)



Coronary artery disease (CAD) and heart failure are major health issues and a leading cause of death. Current medical treatments include beta-blockers, ACE-inhibitors, diuretics, aldosterone-antagonists as well as angiotensin 2 receptor blockers alone or in combination with neprilisyn inhibitors (ARNIs). Within the last 15 years Entresto (approval in 2015, first-in-class ARNI-therapy) is the major new treatment option that has reached market. Although such medications offer a variety of treatment options and guideline proven therapies are available, some patients still run out of options and continue to have severe and debilitating heart failure, resulting in a 5-year survival rate below 50%. Over the past decade novel molecular mechanisms associated with cardiovascular diseases (CVD) have been discovered, in this course cardiac gene therapy with adeno-associated virus (AAV) based vectors became an emerging new platform aiming to treat or (for inherited forms) even to cure still intractable cardiac disorders. However, there is still a high demand for effective gene therapy interventions and for an efficient delivery of the therapeutic cargo to human cardiomyocytes and other target cells of the cardiovascular system.


MRTF-A (myocardin related transcription factor A) has been identified as a new target for a gene therapy approach for CVD and peripheral ischemia that is suitable to improve microvascular growth and function in cardiac as well as in peripheral muscle tissue. MRTF-A has been originally identified as a potent factor for co-activation of serum response factor (SRF) induced target gene expression. It induces gene expression of matricellular proteins CCN1 and CCN2 which promote microvessel growth (CCN1) and vessel maturation (CCN2) by recruitment of pericytes and smooth muscle cells. Thus, in a dual role MRTF-A is promoting functional cardiac muscle neovascularization as well as micro vascularization of peripheral muscle tissue, thereby enabling arteriogenesis and functional improvement of ischaemic muscle tissue. Accordingly, newly formed collaterals show a well-ordered morphology. In contrast to VEGF based approaches these physiological effects are supposed to be not associated with a carcinogenic potential, as MRTF-A induces in vessel maturation by recruitment of pericytes. AAV9-based delivery ensures tropism to cardiac and peripheral muscle cells. A proprietary protocol for enhanced viral transduction and delivery give rise to high efficiencies for targeted gene delivery (up to 100% in large animal models).

Commercial Opportunity

The technology is available for in-licensing or further co-development of the therapeutic approach.

Development Status

Proof of concept has been shown in mice, rabbits and in large animal models. In a pig model for chronic myocardial ischemia MRTF-A transduction induces neovascularization and collateral formation in the region occluded with an implanted reduction stent. In the hibernating pig myocardium MRTF-A transduction results in neovascularisation and formation of collaterals and in an increase in the heart ejection fraction. Accordingly, a clear improvement of myocardial function was shown in resting and pacing pigs 28 and 56 days after transduction.

Patent Situation

National phases have been entered in EP and US (WO2015158667; Priority date: 14.04.2014). “AAV Vectors for vascular gene therapy in coronary heart disease and peripheral ischemia”.

Further Reading

Hinkel et al., Nat. Commun. 2014, Vol. 5, p. 3970-80.


Novel gene therapy approach for cardiovascular diseases