FIELD OF THE DISCLOSURE

The current disclosure provides anti-heparanase compounds for the treatment of diabetes. The anti-heparanase compounds are high affinity, synthetic glycopolymers that result in minimal anticoagulant activity.

BACKGROUND OF THE DISCLOSURE

Diabetes mellitus (DM), often simply referred to as diabetes, is a condition in which a person has a high blood sugar (glucose) level as a result of the body either not producing enough insulin or because body cells do not properly respond to the insulin that is produced.

In healthy persons, blood glucose levels are maintained within a narrow range, primarily by the actions of the hormone insulin. Insulin is released by pancreatic β-cells at an appropriate rate in response to circulating glucose concentrations. The response is modulated by other factors, including other circulating nutrients, islet innervation, and incretin hormones. Insulin maintains glucose concentrations by constraining the rate of hepatic glucose release to match the rate of glucose clearance. Insulin thus enables body cells to absorb glucose, to turn into energy. If the body cells do not absorb the glucose, the glucose accumulates in the blood (hyperglycemia), leading to various potential medical complications such as cardiovascular diseases, kidney failure, retinopathy, and neuropathy if not properly controlled.

Type 1 diabetes is typically characterized by loss of the insulin-producing β-cells of the islets of Langerhans in the pancreas leading to insulin deficiency. This type of diabetes can be further classified as immune-mediated or idiopathic. The majority of Type 1 diabetes is of the immune-mediated nature, where β-cell loss results from T-cell mediated autoimmune attack. There is no known preventive measure against Type 1 diabetes. Most affected people are otherwise healthy and of normal weight when onset occurs.

Type 2 diabetes is characterized by β-cell dysfunction in combination with insulin resistance. The defective responsiveness of body tissues to insulin is believed to involve the insulin receptor. Similar to Type 1 diabetes, an insufficient beta-cell mass is also a pathogenic factor in many Type 2 diabetic patients.

Treatments available for both forms of diabetes involve therapeutic regimens that are difficult to implement and maintain. As both types of diabetes are characterized by the loss of β-cell mass due to cell death, the restoration and preservation of β-cells mass is a major goal in the treatment of diabetes.

Heparanase has been recognized as a regulator of cancer development. Many small molecule anti-heparanase compounds have been developed because of its use as a target for anti-cancer therapy. However, only four carbohydrates have advanced to clinical trials. Because these molecules are heterogeneous in size and sulfation pattern, they have led to nonspecific binding and unforeseen adverse effects, and thus, their translation into clinical application was terminated. However, PI-88, a sulfated oligomannan mixture, was observed among these four carbohydrate molecules to reduce Type 1 diabetes in mice. Because PI-88 displays anticoagulant properties and is unable to sufficiently produce platelets that help clot blood, however, its potential use for diabetic treatment is limited.

SUMMARY OF THE DISCLOSURE

The current disclosure provides high affinity anti-heparanase synthetic glycopolymers that result in minimal anticoagulant activity and protect pancreatic beta cells and islets for the treatment of diabetes.

