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BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering

Gene therapy with phosphodiesterases to treat heart failure

Awarded: NOK 2.8 mill.

Project Manager:

Project Number:

272419

Application Type:

Project Period:

2017 - 2021

Location:

Subject Fields:

In heart failure (HF) patients, the heart is unable to meet the hemodynamic needs, such as during a physical exercise or an emotional stress. The sympathetic nervous system, activated upon exercise or stress, acts on the heart by the release of noradrenaline which activates beta-adrenergic receptors. Once activated, these receptors cause the production of cyclic AMP (cAMP). However, when the body demand stops, the heart returns to its normal activity by a family of enzymes called phosphodiesterases (PDEs). Thus, beta-adrenergic receptors serve as an accelerator and PDEs as a brake. In HF, the accelerator pedal is stuck to the floor and the brakes are ineffective. This project will use a new gene therapy approach to reintroduce different defective/missing types of PDEs into the heart, with the hope to prevent the associated heart rhythm disorders, which are the main cause of death in HF. The Norwegian contribution to the project has been to develop an animal model of heart failure with preserved ejection, to evaluate the effects of the same gene therapy in this type of heart failure.

Regardless of the underlying cause for heart failure (HF), patients show a neurohormonal overactivation in response to a decline in systolic function. This creates a pathophysiological "vicious circle" where chronic activation of beta-adrenergic signalling plays a central role as attested by the beneficial effect of beta-blockers in HF. In contrast, nitric oxide (NO) and natriuretic peptides (NPs) exert favourable effects in HF. The beta-adrenergic pathway results in an increase in cAMP levels to augment cardiac function, whereas NO and NPs signal through cGMP to exert opposite effects. Cyclic nucleotide (CN) levels are tightly regulated by their hydrolysis by phosphodiesterases (PDEs). The PDE superfamily comprises several distinct isoforms that regulate cAMP and cGMP in discrete microdomains of the cardiomyocyte and ensure the specificity of CN signalling in physiological conditions. However, this organization is lost in HF, thus causing further deterioration of the heart. While chronic PDE inhibition failed to show significant beneficial effects in HF treatment, our preliminary results indicate that it is PDE overexpression that has more promising effects. In this proposal, we intend to further validate this hypothesis and assess whether overexpression of specific PDEs in cardiomyocytes can prevent/reverse HF. To do so, the consortium will test whether gene therapy with cardiac targeted overexpression of three different PDE isoforms can restore CN compartmentation, prevent maladaptive cardiac remodelling and constitute a new therapeutic approach for HF.

Activity:

BEHANDLING-God og treffsikker diagnostikk, behandling og rehabilitering