Trialling a new enzyme inhibitor

The persistently high blood glucose levels associated with diabetes can, over time, cause damage to blood vessels that result in so-called diabetes-related complications. Preventing or reducing diabetes-related complications in the kidney is the focus of some of the work currently underway at the Baker IDI.

A potential new treatment for diabetic kidney disease is about to go into an international Phase II clinical trial and Australian patients will make up some of the participants.

The ‘Nox team’ - (L to R) Miss Elyse DiMarco, Professor Karin Jandeleit-Dahm, Dr Stephen Gray and Mr Jay Chandra Jha.

Discovered through research conducted by Professor Karin Jandeleit-Dahm, Head of the Diabetes Complications Division at the Baker IDI Heart and Diabetes Institute, in collaboration with Prof Harald Schmidt from the University of Maastricht in Holland, the treatment inhibits a specific enzyme known to cause kidney injury in diabetes - NADH oxidase enzyme 4 (NOX4).

Diabetic nephropathy

Diabetic-related kidney disease or diabetic nephropathy is the major cause of end-stage renal disease in the Western world. Diabetes also increases the risk of cardiovascular disease, which is amplified if kidney disease is present, and diabetic retinopathy is another consequence of this condition.

The standard treatment option for kidney nephropathy (ACE inhibitors) targets the renin-angiotensin system and aims to reduce blood pressure by blocking angiotensin. This treatment halts the disease to some degree, but it is not a cure.

“Some people progress to requiring dialysis or kidney transplantation more quickly than others,” said Jandeleit-Dahm, “although it is not understood why.”

Reduced disease in knock-out mice

Jandeleit-Dahm's research builds on earlier work in which the team identified a related enzyme, NOX1, to be an important target in preventing cardiovascular and eye disease in diabetes, as demonstrated in a collaboration with Professor Jennifer Wilkindon-Berka from Monash University.

“The NOX family of enzymes play a role in various complications,” Jandeleit-Dahm explained. “They are very important in the kidney and vascular systems. We have previously identified NOX1 in the aorta and demonstrated its importance in plaque formation and atherosclerosis, which leads to heart attacks and stroke.”

“The NOX enzymes are important in generating oxidative stress in the kidney,” she said. “We used knock-out mice for NOX1 and NOX4, which were developed by our collaborator at the University of Maastricht, Professor Harald Schmidt, and showed that when these mice were made diabetic they underwent a reduction in albuminuria, kidney fibrosis and inflammation.”

Inhibiting oxidative stress

Albuminuria, or an increased level of albumin in the urine, is a hallmark of developing and ongoing kidney disease.

“We have also been looking at the expression or upregulation of the NOX genes and, using our Canadian colleagues’ state-of-the-art HPLC technology, we measured the amount of reactive oxygen species being produced in the NOX4 knock-out mice,” Jandeleit-Dahm said.

This work demonstrated that the NOX4 gene is important in mediating kidney disease in diabetes, whereas NOX1 is pivotal in mediating blood vessels and eye disease in diabetes.

“We have been collaborating with Genkyotex, a Swiss biotech company who have developed an inhibitor that blocks NOX1 and NOX4,” Jandeleit-Dahm continued. “When we treated mice with the inhibitor the results paralleled the studies in the knock-out mice for NOX4 with respect to kidney disease.”

The research, which Jandeleit-Dahm’s team presented at the 22nd World Diabetes Congress held in Melbourne at the end of 2013, has been published online in the Journal of the American Society of Nephrology.

Entering a clinical trial

The compound has entered an international Phase II clinical study for patients with type 2 diabetes-related kidney disease who have high levels of albuminuria. The Baker IDI is participating in the trial, which will initially assess safety and efficacy of the inhibitor on top of maximal treatment with the current standard treatment, ACE inhibitors or angiotensin receptor blockade.

“We want to investigate if there is a decrease in the level of albumin in the urine of trial participants,” said Jandeleit-Dahm. “A reduction in albuminuria also translates to a reduction in the risk of further progression of kidney disease and in cardiovascular disease risk.”

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