Diabetic nephropathy therapies

a nephropathy and diabetes technology, applied in the field of diabetes nephropathy therapies, can solve the problems of reducing kidney function, hypertension, renal failure, compromising quality of life, etc., and achieve the effect of inhibiting and preventing these processes

Inactive Publication Date: 2005-09-29
FIBROGEN INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] The present invention addresses these needs by identifying the role of CTGF in various processes associated with the development and progression of renal disorders such as, e.g., diabetic nephropathy, and by providing methods for inhibiting and preventing t

Problems solved by technology

Renal disorders can lead to reduced kidney function, hypertension, and renal failure, seriously compromising quality of life, sometimes requiring dialysis and in certain circumstances, kidney transplantation.
However, although ACE inhibitors have been shown to delay renal decline in patients with Type 1 diabetes, the renoprotective effect of these agents in patients with Type 2 diabetes is less clear.
Further, while glycemic and blood pressure control therapies significantly decrease the morbidity and mortality associated with diabetic nephropathy by delaying progression of associated pathologies, such conventional therapies do not adequately halt the progression of the disease and thus fail to provide a complete therapeutic effect.
In addition, administration of ACE inhibitors or ARBs, the current standard of care, are not universally effective and only minimally delay, but do not remove, the need for kidney transplantation.
Such therapeutic approaches, however, have not provided amelioration of all aspects of renal pathology (e.g., altered and impaired renal function and structure) associated with diabetic nephropathy.
For example, inhibition of TGFβ as a therapeutic target for di

Method used

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Examples

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example 1

Treatment of Early Stage Features of Diabetic Nephropathy

[0109] The methods of the invention were used to demonstrate broad-spectrum efficacy in an animal model for certain aspects of early stage diabetic nephropathy as follows. Eight-week-old mice having a loss-of-function mutation in the leptin receptor (Ob-R; encoded by the db gene) were obtained from Harlan, Indianapolis Ind. These db / db mice serve as an animal model of obese type 2 diabetes, and, in particular, a model of obese type 2 diabetic nephropathy characterized by early aspects of diabetic nephropathy, including, for example, kidney hyperfiltration and proteinuria with minimal development of interstitial fibrosis. This is an animal model of early stage diabetic nephropathy rather than late stage diabetic nephropathy, as evidenced by the minimal development of interstitial fibrosis. Homozygous db / db (diabetic) are hyperglycemic at 8 weeks of age. Homozygous db / db (diabetic) and heterozygous db / +(non-diabetic) animals we...

example 2

CTGF Implicated in Early Stage Features of Progressive Vitreoretinal Disorders

[0117] The association between CTGF and ocular disease, including retinal disorders, has been previously established. (See, e.g., International Publication No. WO 03 / 049773.) Here, the relationship between ocular concentrations of CTGF and VEGF and the degree of neovascularization and fibrosis were examined to determine the correlation, if any, between CTGF and VEGF expression in vitreous. A correlation would be suggestive of CTGF involvement in both early stage and late stage aspects of ocular disorders. Undiluted vitreous samples (0.5 to 1 ml) were obtained at the start of a pars plana vitrectomy in patients with proliferative vitreoretinopathy (PVR), proliferative diabetic retinopathy (PDR), macular pucker, or macular hole. Samples of vitreous fluids were collected in sterile tubes, immediately frozen in dry ice, and stored at −80° C. until assayed for CTGF and VEGF.

[0118] Neovascularization associate...

example 3

Treatment of Late Stage Features of Diabetic Nephropathy

[0122] The effect of anti-CTGF therapy was examined in an animal model of late stage diabetic nephropathy. As has been previously described using this animal model, rats with diabetes mellitus exhibited high susceptibility to unilateral renal ischemia reperfusion, resulting in rapidly progressive nephropathy and end-stage renal failure, associated with development of fibrosis, atrophy of the kidney, and severely compromised glomerular filtration rate. (See, e.g., Melin et al. (1997) Kidney Int 52:985-991.) In this animal model of diabetes mellitus, ischemia severely impaired kidney function in diabetic rats. In this animal model, the renal effects on kidney function and pathology of hyperglycemia and ischemia are similar to those observed in human late stage diabetic nephropathy and end-stage renal disease (ESRD).

[0123] Diabetes mellitus was induced in male Sprague Dawley rats by a single i.v. dose of streptozotocin (STZ) (50...

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Abstract

The present invention relates to methods and compounds for treating specific early stage aspects and late stage aspects of diabetic nephropathy. Methods and compounds for treating various physiological features associated with early stage and with late stage diabetic nephropathy are also provided.

Description

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60 / 544,121, filed on 11 Feb. 2004; U.S. Provisional Application Ser. No. 60 / 561,018, filed on 8 Apr. 2004; U.S. Provisional Application Ser. No. 60 / 578,401, filed on 9 Jun. 2004; and U.S. Provisional Application Ser. No. 60 / 620,802, filed on 20 Oct. 2004, each of which is incorporated by reference herein it its entirety.FIELD OF THE INVENTION [0002] The present invention relates to methods and compounds for treating specific early stage aspects and late stage aspects of diabetic nephropathy. Methods and compounds for treating various physiological features associated with early stage and with late stage diabetic nephropathy are also provided. BACKGROUND OF THE INVENTION [0003] A renal disorder is any alteration in normal physiology and function of the kidney. Renal disorders can result from a wide range of acute and chronic conditions and events, including physical, chemical, or biological injury, in...

Claims

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Application Information

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IPC IPC(8): A61K31/00A61K38/00A61K38/55A61K39/395C07K16/22
CPCA61K31/00A61K38/556A61K39/395A61K2039/505C07K16/22A61K2300/00A61P13/12A61P3/10
Inventor FLYVBJERG, ALLANGUO, GUANGJIELIU, DAVID Y.NEFF, THOMAS B.OLIVER, NOELYNN A.USINGER, WILLIAM R.WANG, QINGJIAN
Owner FIBROGEN INC
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