ACE2 agonist with anti-fibrotic and anti-inflammatory activity, and that controls blood glucose levels in diabetic mouse models; potential to treat diabetic organ disease.

About

Background The coordinated activity of the renin angiotensin system (RAS) is key to control of many physiological functions. Physiological outcomes of the RAS depend on the balanced synthesis and breakdown of the effector peptide angiotensin II, which when produced in excess contributes substantially to inflammation and fibrosis, and angiotensin 1-7, which mediates the counter-regulatory arm of RAS by exerting opposing effects. Angiotensin converting enzyme-2 (ACE-2) – which converts angiotensin II to angiotensin 1-7 – thus plays a critical role in regulating RAS. In addition to the well-characterised role in inflammation and fibrosis, RAS also plays a role in glucose homeostasis. Chronic overactivation of the RAS has been identified as a key driver in diseases such as cardiovascular and kidney disease. In the case of the kidneys, renal inflammation, fibrosis, and chronic kidney disease result, which ultimately progress to kidney failure. However, even where disease is not a direct result of RAS dysregulation, modulation of the counter-regulatory arm has therapeutic potential, with administration of synthetic angiotensin 1-7 found to reduce kidney fibrosis and inflammation in diabetic kidney models, albeit limited by its short half-life.   The technology Researchers at The University of Queensland (UQ) have developed a 10 amino acid peptide (2A) that potently stimulates ACE-2, effectively re-balancing RAS towards the ‘protective’ arm. The peptide offers a novel therapeutic approach to intercept the progression of a number of high value inflammatory-related conditions, with particular potential to treat diabetes and diabetic organ disease, offering two-pronged protection by: (1) decreasing inflammation and fibrosis, and (2) moderating blood glucose levels. With diabetes remaining the leading cause of chronic kidney disease and poor management of the disease – particularly blood glucose levels – shown to drive a number of other complications including cardiovascular and kidney disease, ACE-2 agonists have the potential to meet a number of high unmet clinical and market needs. Proof of concept Data collected in both in vitro and in vivo models demonstrates that 2A has strong anti-inflammatory and anti-fibrotic effects. In cultured endothelial cells, 2A prevents the Ang-II induced expression of fibrotic and inflammatory markers. In mouse models of severe diabetes, 2A attenuates kidney fibrosis and inflammation and further, effectively controls blood glucose levels, completely preventing the substantial (~35%) increase in blood glucose observed in diabetic mice. Notably, that reduction in blood glucose is not achieved through increased excretion of glucose (as observed with current SGLT2 inhibitors in the treatment of type 2 diabetes), suggesting that 2A moderates blood glucose via a novel mode — increasing glucose metabolism. Together, these effects result in a drastic increase in survival of severely diabetic mice. Additional in vivo experiments on the effects of 2A on kidney fibrosis and inflammation in commercially relevant mouse models of diabetic nephropathy are underway. Further, the research team has expertise and access to a number of other in vivo disease models, including for heart failure (e.g. MST1) and type 2 diabetes (eg. db/db). Potential therapeutic benefit of 2A treatment has also been demonstrated in models of lung- and neuro- inflammation.

Key Benefits

• Potential first-in-class therapy: ACE-2 agonist; • Novel mode of organ-protective action, with PoC data in diabetes and diabetic nephropathy, and potential to treat cardiovascular and kidney disease; • Stable peptide: detected in multiple organs after 24 hours, including kidney and heart; • Safe: no observed adverse effects in mice.

Applications

Therapeutic to treat diabetes mellitus, including diabetic complications such as cardiovascular disease and organ damage, particularly the kidneys.

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