Treatment of disorders associated with elevated blood glucose or blood pressure

a technology of connective tissue growth factor and extracellular matrix, which is applied in the direction of drug composition, metabolic disorder, cardiovascular disorder, etc., can solve the problems of body's ability to adequately, degradation or impairment of kidney function, and the inability of the body to meet the needs of the body, so as to reduce the overproduction of extracellular matrix and inhibit the activity of ctgf

Inactive Publication Date: 2005-06-23
RISER BRUCE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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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 CTG...

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...

Method used

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  • Treatment of disorders associated with elevated blood glucose or blood pressure
  • Treatment of disorders associated with elevated blood glucose or blood pressure
  • Treatment of disorders associated with elevated blood glucose or blood pressure

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0172] CTGF-Induced Changes In Extracellular Matrix Production Of Mesangial Cells. To determine the effects of exogenous CTGF on mesangial cell production of the extracellular matrix, serum-depleted cells were exposed for 48 hours to media containing 20 ng / ml of rhCTGF. For comparison purposes, additional cultures were incubated in media without exogenous CTGF, but containing either 2 ng / ml of TGF-β, or 20 mM glucose. As anticipated, exogenous TGF-β and the high glucose concentration increased the amount of secreted fibronectin by 23 and 30%, respectively, over that of controls as shown in FIG. 1A. The presence of exogenous CTGF in the media also effectively stimulated fibronectin secretion by 45%. Like fibronectin, the quantity of secreted collagen type I was also increased by 64% CTGF, as well as by 50% TGF-β or 22% high glucose as shown in FIG. 1B.

example 2

[0173] Renal And Mesangial Cell CTGF Expression: Regulation By TGF-β. It was determined whether cultured rat mesangial cells expressed CTGF mRNA, and the results were compared to those from whole kidney. Northern analysis demonstrated a single 2.4 kb CTGF transcript in mesangial cells and whole kidney, but in contrast no detectable message was evident in cultured kidney fibroblasts as demonstrated in FIG. 2. When compared to other tissues, the most abundant expression was in the kidney, being approximately 20-fold higher than in the brain.

[0174] To determine if TGF-β was a regulatory factor in mesangial cell expression of CTGF message, cells were serum-depleted, exposed to 2 ng / ml of TGF-β for 24 hours, the mRNA was then probed. Changes in TGF-β transcript levels were also monitored. Exogenous TGF-β exposure increased the expression of CTGF mRNA greater than 4-fold as shown in FIG. 3A and FIG. 3B, whereas TGF-β mRNA increased 80% (see FIG. 3A and FIG. 3C). To determine whether CTGF...

example 3

[0176] Detection Of CTGF In Mesangial Cells. The CTGF protein detected In mesangial cell cultures above represents free molecules present in the media. The existence of a heparin binding domain within CTGF suggests that a substantial portion of the synthesized and released protein exists bound to proteoglycans, or to fibronectin, present on the cell surface or in the extracellular matrix. To ascertain whether this was the case, and to determine the time course for appearance of CTGF in the extracellular environment under unstimulated conditions, mesangial cell cultures were serum-deprived and then fresh maintenance media containing 50 μg / ml of sodium heparin was added. Conditioned media were collected after defined incubation periods and the majority of the sample pooled and heparin-sulfate precipitated. Immunoblotting of the 4 hour samples produced faint CTGF bands at approximately 36 and 39 kD (see, FIG. 5A). The intensities of these bands increased sharply by 24 hours and remaine...

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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...

Claims

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Application Information

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IPC IPC(8): A61K31/7088A61K38/00A61K38/28A61K39/395A61K45/00A61K48/00G01N33/50A61P3/10A61P7/04A61P9/12A61P13/12A61P19/04C07K16/22C12Q1/68G01N33/53G01N33/531G01N33/566G01N37/00
CPCA61K38/00A61K39/395C07K16/22C07K2317/73A61K2300/00A61P13/12A61P19/04A61P7/04A61P9/12A61P3/10
Inventor RISER, BRUCEDENICHILO, MARK
Owner RISER BRUCE
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