SBIR-STTR Award

Vascular disease is the principal cause of morbidity and mortality in patients with diabetes, leading to nephropathy, retinopathy, neuropathy, and ischemic disease. Hyperglycemic damage to vascular endothelial cells is a major cause of these vascular complications of diabetes. This endothelial dysfunction is caused by oxidative stress induced by hyperglycemia, resulting in both the increased production of reactive oxygen species (ROS) and decreased bioavailability of nitric oxide (NO). Hyperglycemia also causes similar oxidative stress in renal mesangial cells, which leads to mesangial matrix expansion, glomerosclerosis, and renal functional impairment. We have developed a novel drug for treatment of hyperglycemia induced endothelial and mesangial cell dysfunction. OX029 is a bifunctional NO-donor/SOD-mimetic which is a derivative of lipoic acid, The major goals of this proposal are to (1) determine the efficacy of OX029 to prevent endothelial dysfunction and renal injury in the diabetic streptozotocin-treated rat, and (2) design and synthesize 20 novel analogs of OX029 and test their efficacy in isolated blood vessels and cultured renal mesangial cells exposed to hyperglycemia. If OX029 is efficacious in preventing renal injury in STZ-diabetic rats, we plan to submit a Phase II grant to: (1) test one or two OX029 analogs for prevention of diabetic nephropathy in vivo, (2) expand the in vivo studies in STZ-diabetic rats to a long term study (6-9 months) to include other endpoints of renal pathology, such as histology and morphometry, glucose tolerance and insulin sensitivity, and renal function, and (3) expand the in vivo studies to include another animal model of diabetes, the db/db mouse which spontaneously develops type II diabetes. The long-term commercial goal is to develop an orally active drug which can be given to both type I and type II diabetics to attenuate the renal damage caused by chronic hyperglycemia, and also attenuate other vascular complications of diabetes.

Thesaurus Terms:
biomimetics, chemoprevention, diabetic nephropathy, drug design /synthesis /production, drug screening /evaluation, kidney disorder chemotherapy, nitric oxide, superoxide dismutase analog, antioxidant, diabetes mellitus, diabetes mellitus therapy, disease /disorder model, free radical oxygen, free radical scavenger, hyperglycemia, kidney cell, kidney function, kidney pharmacology, oxidative stress, short chain fatty acid, vascular endothelium, vasomotion laboratory rat, tissue /cell culture

Vascular disease is the principal cause of morbidity and mortality in patients with diabetes, leading to nephropathy, retinopathy, neuropathy, and ischemic disease. Hyperglycemic damage to vascular endothelial cells is a major cause of these vascular complications of diabetes. This endothelial dysfunction is caused by oxidative stress induced by hyperglycemia, resulting in both the increased production of reactive oxygen species (ROS) and decreased bioavailability of NO. Hyperglycemia also causes similar oxidative stress in renal mesangial cells, which stimulates the production of TGFa1 and extracellular matrix proteins, leading to matrix expansion, glomerosclerosis, and renal functional impairment. We have developed a novel drug (OX029) for treatment of hyperglycemia-induced endothelial dysfunction and diabetic nephropathy. OX029 is a bifunctional NO-donor/SOD-mimetic which is a derivative of a-lipoic acid. The Phase I study demonstrated that daily i.p. administration of OX029 (30 mg/kg) for 2 months to diabetic streptozotocin-treated (STZ) rats completely prevented surrogate markers for diabetic nephropathy (albuminuria) and endothelial dysfunction (impaired acetylcholine-induced relaxation of precontracted aortas). This is compelling evidence that OX029 may be an effective drug for the treatment of diabetic nephropathy and the vascular complications of diabetes in human. For OX029 to be useful as a drug, however, it must be safe, orally active, and have sustained efficacy over a long period of hyperglycemia. The primary objective of this Phase II study is to determine the long-term efficacy of oral administration of OX029 in preventing diabetic nephropathy and endothelial dysfunction in animal models of type 1 diabetes (STZ-treated rats) and type 2 diabetes (genetically obese db/db mice). This study will determine the efficacy of OX029 to prevent the damaging effects of hyperglycemia, including nephropathy (mesangial matrix expansion, glomerulosclerosis, increase in glomerular basement membrane thickness, increased glomerular TGFa expression and collagen IV deposition, increased urinary excretion of albumin, TGFa, and collagen IV), and loss of endothelium-dependent, nitric-oxide mediated vasodilation. This will require developing scale-up protocols for the large-scale synthesis of 250 grams of OX029, developing a stable formulation for mixture in dietary chow, and determination of an appropriate dosing regimen for administration in the diet. A related objective will be to determine the pharmacokinetic properties of OX029 in rats and mice, and the physiochemical properties of OX029. Additional medicinal chemistry will be done to improve the PK properties of OX029 and extend the plasma half-life of the oral formulation. It is hoped that the successful outcome of these studies will provide the primary data for submission of an IND for subsequent study of OX029 in humans. The long-term objective of this project is the development of an orally active drug (OX029) for diabetics which can prevent or reverse the damaging effects of chronic hyperglycemia on the vasculature and the kidney. Diabetes is the most common cause of kidney failure in the U.S., and there are approximately 150 million Americans living with kidney failure as a result of diabetes. The cost of care for diabetic patients with kidney failure was estimated in 2003 to be $12-15 billion. Neurox has developed a drug, OX029, which was shown in the Phase I SBIR study to prevent kidney damage (nephropathy) in a rat model of diabetes. The Phase II grant will determine if OX029 administered orally can prevent the nephropathy in long-term studies in models of type 1 diabetes (rats) and type 2 diabetes (mice). The goal is to develop OX029 for the treatment of diabetic nephropathy in humans, and significantly reduce the number of diabetic patients that develop kidney failure