Novel Apelin Receptor Agonists Provide for Improved Metabolic Control and Weight Loss (U370)

Tuesday, 18 October 2016

Researchers in the Biomedical Sciences Research Institute at Ulster University have demonstrated that synthetically derived analogues of apelin-13 improve metabolic status and reduce body weight in a diet-induced, insulin resistant animal model of type 2 diabetes.

Problem Being Solved

Diabetes mellitus currently affects more than 3 million people in the UK (80,000 in N.I.) and some 850,000 who are unaware that they have the disease, with some 387 million cases diagnosed globally. Diabetes treatments at present take up about 10% of the NHS budget (£9.8 billion) and much of this is concerned with treatment of the complications resulting from poor glycaemic control and the consequences of hyperglycaemia. In addition to abnormal insulin secretion, poor insulin action also contributes to hyperglycaemia leading to disease complications. This healthcare cost is projected to rise to an estimated 17% of the NHS budget (£16.9 billion) by 2035.

Technology

Native apelin, a circulating cytokine, is secreted from the adipocyte and is degraded via ACE2 yielding cleavage products that include apelin-13.  Preliminary results form our labs have shown that apelin-13 is rapidly degraded in plasma, whereas novel analogues comprised of various amino acid substitutions and/or modifications improve the stability drastically with fatty acid derivatives providing for an estimated 24hr ½ life, based upon intact peptide over time. Following acute in vivo studies in high-fat fed NIH Swiss mice, fatty acid analogues were shown to be the most promising when assessed on their ability to lower blood glucose and improve glucose tolerance and such activity was retained and even surpassed up to 16 h. Chronic studies (28d) aimed at assessing and comparing the glucose-lowering and insulinotropic effects of Ulster’s lead fatty acid analogue with the longer acting GLP-1 agonist, lirgalutide were conducted.  Once daily administration of Ulster’s lead compound was shown to induce a significant decrease in bodyweight (approx. 7%) at day 16 compared to liraglutide which only resulted in a 3% decrease. Ulster lead analogue was seen to significantly reduce circulating blood glucose and increase plasma insulin as well as improve glucose tolerance and plasma insulin excursion.  The peptide significantly improved insulin sensitivity and reduced HbA1c  levels towards lean controls greater than liraglutide.  In addition, compounds were shown to significantly lower plasma triglyceride levels, total cholesterol levels as well as HDL-cholesterol levels compared to lean control and high fat fed mice, suggesting an improvement in the lipid profile.

Benefits/Applications

              Lead peptide analogues of the apelin receptor (APJ) represent a novel class of molecules as potential treatment for Type 2 diabetes and associated obesity.

              Peptides are short in length (e.g. 10-15 amino acids) and have been designed to withstand degradation with lead analogues exhibiting extended half-life compared to native apelin-13.

              Lead analogues exhibit a comparable if not superior antidiabetic profile to the marketed drug, liraglutide (Victoza®).

              Unlike liraglutide, lead analogues exhibit impressive changes in lipid profiles, decreasing cholesterol and triglycerides, as well as increasing HDL and lowering LDL.

              As APJ is also highly expressed in the heart, our agonists can be expected to have extra benefit as for treatment of the cardiovascular complications of obesity-diabetes.

 

Opportunity/Partnership Sought

Ulster University is actively seeking a strategic partner to assist in the further development of this exciting technology, providing a route to market for the safe and effective treatment of type 2 diabetes and associated obesity.

The University is open to a variety of models for collaboration including sponsored research, out-licensing and co-development.

In addition, the inventors of this technology are able to provide valuable know-how in order to assist with its successful commercialisation.

 

For more information, please contact:

Dr Oonagh Lynch

Technology Commercialisation Executive

Research & Impact

Tel: +44 (0) 28 9036 6707

Mob: +44 (0) 77 6536 3191

Email:ot.lynch@ulster.ac.uk