Treatment of disorders associated with elevated blood glucose or blood pressure

Abstract

The present invention relates to methods for treating or delaying the onset of pathologies associated with elevated blood glucose and / or elevated blood pressure. The methods are directed to modulating, regulating, or inhibiting the expression or activity of Connective Tissue Growth Factor (CTGF) or fragments thereof.

Description

[0001] This application is a continuation of U.S. patent application Ser. No. 10 / 687,479, filed Oct. 16, 2003, which is a continuation of U.S. patent application Ser. No. 09 / 392,024, filed on Sep. 8, 1999; and claims the benefit of U.S. Provisional Application Ser. No. 60 / 099,471, filed on Sep. 8, 1998; and U.S. Provisional Application Ser. No. 60 / 112,855, filed on Dec. 16, 1998; all of which are incorporated by reference herein in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to the role of Connective Tissue Growth Factor (CTGF) in the production of extracellular matrix. More specifically, the invention relates to methods of detecting, preventing, and treating kidney fibrosis and other conditions associated with overproduction of the extracellular matrix by targeting CTGF. BACKGROUND OF THE INVENTION [0003] Kidney Diseases And Disorders. The kidney functions to separate waste products from the blood, regulate acid concentration, and maintain water balan...

AI Technical Summary

Benefits of technology

[0029] In another aspect, the present invention provides a method for treating and preventing complications associated with renal disorders, particularly, diabetes and hypertension, wherein antisense oligonucleotides which specifically bind to CTGF mRNA are used to interrupt expression of the protein product. The antisense oligonucleotides have a sequence capable of binding specifically with any polynucleotide sequences encoding CTGF or fragments thereof.

[0030] In yet a further embodiment of the present invention, a method is provided in which small molecules are used to inhibit the activity of CTGF or its active fragments by blocking the binding of CTGF to its receptor, inhibiting CTGF activity and thus thereby reducing the overproduction of the extracellular matrix associated with the onset and / or progression of renal disorders, including diabetes and hypertension.

Problems solved by technology

Any degradation in kidney function can interfere with the body's ability to adequately remove metabolic products from the blood, and can disrupt the body's electrolyte balance.

In its most severe forms, degradation or impairment of kidney function can be fatal.

A number of conditions can lead to chronic renal failure, a decline in kidney function over time.

Fibrosis involves altered formation or production of fibrous tissue, and can result in the overproduction and increased deposition of extracellular matrix components.

In fibrosis, overproduction and increased deposition of ECM materials can result in thickening and malformation of various membranous and cellular components, reducing local flexibility and surface area of the affected site, and impairing a number of bodily processes.

Kidney fibrosis can be manifested as a diffuse thickening of kidney membranous components, the accumulation and expansion leading to a loss of filtration surface area and a corresponding disruption in the body's electrolyte composition and acid-base balance.

Diabetes produces a number of debilitating and life-threatening complications.

This pathological deposition results in impaired filtration, leading to renal failure, a condition requiring transplantation or life-long dialysis.

Hyperglycemia may be damaging, in great part as increased concentrations of glucose stimulate ECM accumulation by mesangial cells.

For example, in diabetes, an early impairment of normal blood pressure dampening occurs at the glomerular afferent arteriole, resulting in the exposure of glomerular capillaries to large moment-to-moment variations in systemic blood pressure.

Further, no connection between CTGF mRNA levels and the production and deposition of ECM, and no quantitative method for detecting renal disorders or diseases, including diabetes, involving a determination of CTGF levels in samples, and did not identify CTGF-expressing cells.

Kidney failure is a serious condition requiring extreme treatment such as hemodialysis or transplantation.

Hypertension, for example, might be undetectable by a patient in early stages, but can be deadly if not identified, monitored, and treated.

For example, kidney failure resulting from progressive glomerulosclerosis is the leading cause of morbidity and mortality among patients with type I, or juvenile, diabetes mellitus.

Nevertheless, this treatment is not justified in all newly diagnosed diabetic patients because only approximately 30-35% of these develop progressive kidney disease, and the long-term side effects of these drugs are uncertain.

However, the mechanism of renal protection, and, as noted above, the long-term side effects of this treatment are not fully understood.

Furthermore, ACE inhibitors have been shown to negatively interact with nonsteroidal anti-inflammatory drugs.

However, the actual level of microalbuminuria may not necessarily predict the development of overt nephropathy, particularly among patients with a long duration of diabetes.

In addition, since by the time microalbuminuria is detected, structural renal lesions are already present, the effectiveness of treatment to slow progression may be substantially reduced.

No current research has focused on the modulation of CTGF expression or activity as a means of preventing or treating kidney fibrosis.

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