Gene discovery paves way for treatment of potentially fatal vascular complications in people with diabetes

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An Australian-Dutch research team led by Prof Karin Jandeleit-Dahm from the Baker IDI Heart and Diabetes Institute, Melbourne and Prof Harald Schmidt from the Maastricht University, has confirmed the role of a specific enzyme in the accelerated development of diabetic atherosclerosis. By suppressing the gene coding for this enzyme or inhibiting the activity of the enzyme with a new drug, researchers were able to significantly reduce the development of plaques which can block arteries, paving the way for a new approach to prevention and treatment of cardiovascular disease in people with diabetes.

Commenting on the findings, Baker IDI’s Head of Diabetic Complications research Professor Jandeleit-Dahm said, “This is a very important break-through because cardiovascular disease is the leading cause of death for diabetic patients .”

The research is funded in part by a grant from JDRF, the world’s largest charitable funder of type 1 diabetes research.

Diabetic patients are susceptible to vascular complications such as atherosclerosis – a condition that involves thickening of the artery walls through a build-up of cholesterol-rich plaques. As a result, people with diabetes are at increased risk of stroke, myocardial infarction and death . The precise causes of this accelerated development of atherosclerosis have remained elusive but oxidative stress in response to high blood sugar appears to play a role.

The joint research initiative discovered that a gene known as NOX1 was associated with toxic amounts of oxygen radicals in the walls of blood vessels, which along with other inflammatory chemicals, leads to atherosclerotic plaque development.

Professor Schmidt said, “After zeroing-in on NOX1 as the main cause of oxidative stress in diabetes, we were able to examine the effects of suppressing this enzyme through gene manipulation or with a new therapeutic drug. What we discovered was that by inhibiting NOX1 in diabetic mice, we were able to significantly improve vascular health and prevent the development of atherosclerotic plaques.”

The researchers are collaborating with Genkyotex, a Swiss-based biotechnology company, which has developed a NOX1 and 4 inhibitor known as GKT137831. Mice treated with the NOX inhibitor demonstrated a dramatic reduction in vessel damage and plaque development, providing a new therapeutic approach to reduce oxidative stress in people with diabetes.

“Having narrowed our target, we can now focus on blocking NOX1 with the aid of pharmacological therapies. Our ultimate goal is to translate these findings into a clinical treatment to reduce the burden of disease in diabetic patients,” said Professor Jandeleit-Dahm.

Following the successful completion of clinical safety studies in healthy human subjects, a Phase II clinical study of GKT137831 in patients with diabetic nephropathy is now planned by Genkyotex. (Baker IDI Heart & Diabetes Institute)