Diabetic nephropathy therapies

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...

AI Technical Summary

Benefits of technology

[0025] In another aspect, the invention encompasses a method for reducing or preventing kidney weight gain in a subject having or at risk for having diabetes or diabetic nephropathy, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF.

[0031] In yet a further embodiment, the invention provides a method for preventing, reducing the risk of, or delaying the onset of diabetic complications in a subject at risk for developing such complications, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF. In various embodiments, the diabetic complications include at least one complication selected from the group consisting of increased creatinine clearance, increased or decreased glomerular filtration rate, glomerular basement membrane thickening, glomerular hyperfiltration, glomerular hyperperfusion, glomerular hypertrophy, increased urinary albumin excretion, microalbumnuria, macroalbuminuria, increased BUN levels, increased inulin clearance, kidney weight gain, and impaired kidney function.

[0034] Methods for treating progressive renal failure in a subject the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, are provided in one embodiment. In another embodiment, the invention provides a method for reducing the risk or delaying the onset of development of microalbuminuria in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF. In an additional embodiment, a method for reducing the risk or delaying the onset of development of macroalbuminuria in a subject, the method comprising administering to the subject a therapeutically effective amount of an agent that inhibits CTGF, is also provided.

[0037] As summarized in the preceding description, the invention relates to the discovery that anti-CTGF therapy is effective in treatment or prevention of various physiological features of early stage and late stagy diabetic nephropathy. Accordingly, it is contemplated that the present invention provides methods for treating or preventing a renal disorder associated with at least one of the features selected from the following: increased creatinine clearance; increased glomerular filtration or glomerular hyperfiltration; proteinuria; increased urine albumin excretion; increased glomerular volume; glomerular hypertrophy; increased kidney weight; glomerular basement membrane thickening; reduced glomerular filtration rate; increased BUN levels; and increased inulin clearance. In each case, the methods comprise administering to a subject in need of such treatment an effective amount of an agent that inhibits CTGF. These methods specifically cover administration to a subject of the agent that inhibits CTGF for the express purpose of preventing progression to or development of any one of the above-described complications.

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 diabetic nephropathy was not effective at attenuating albuminuria in db / db mice, despite the beneficial effects such treatment had on glomerular matrix expansion.

(See Ziyadeh et al, supra) In addition, while administration of anti-VEGF antibodies to diabetic db / db mice provided benefit to diabetes-associated increased permeability in the kidney, only minimal beneficial effects on mesangial expansion were observed.

Therefore, although such therapies offer promise, alone or in combination, none has resulted in amelioration of both early (e.g., glomerular hyperfiltration, increased glomerular filtration rate.

In addition to the above deficiencies, current therapies for diabetic nephropathy have limited applicability / efficacy due to lack of specificity.

In particular, VEGF— or TGFβ-targeted therapies may compromise the beneficial activities of these growth factors, such as angiogenesis, tumor suppression, and proper immune system development.

For example, while TGFβ has been associated with development of fibrosis, it is also an important mediator of immune development and tumor suppression, suggesting that inhibition of TGFβ might have unwanted and potentially adverse secondary effects.

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