Methods for treating conditions associated with the accumulation of excess extracellular matrix

Abstract

The present invention is methods and compositions for reducing and preventing the excess accumulation of extracellular matrix in a tissue and / or organ or at a wound site using a combination of agents that inhibit TGFβ, or using agents that inhibit TGFβ in combination with agents that degrade excess accumulated extracellular matrix, or at least one agent that degrades excess accumulated extracellular matrix. The compositions and methods of the invention are used to treat conditions such as fibrotic diseases and scarring that result from excess accumulation of extracellular matrix, impairing tissue or organ function or skin appearance in a subject.

Description

RELATIONSHIP TO OTHER PATENTS[0001]This application is a continuation-in-part of U.S. Ser. No. 09 / 869,820, filed Jul. 5, 2001, and a continuation-in-part U.S. Serial No. patent application Ser. No. 10 / 887,378, filed Jul. 8, 2004, the contents of which are incorporated by reference herein, in their entirety.[0002]Throughout this application, various publications are referenced within parentheses. The disclosures of these publications are hereby incorporated by reference herein in their entireties.GOVERNMENT RIGHTS[0003]The work described here was supported, at least in part, by grants from the National Institutes of Health Grants DK 49374 (5R01DK49374), DK 43609 (2R37DK043609) and DK 60508. The United States government may, therefore, have certain rights in the invention. Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe t...

AI Technical Summary

Benefits of technology

[0029]Accordingly, the present invention provides methods for preventing or reducing the excess accumulation of extracellular matrix (ECM) associated with fibrotic conditions by inhibiting TGFβ, using a combination of agents that inhibit TGFβ, or by using a combination of agents to inhibit TGFβ and agents that cause the enhanced degradation of excess accumulated ECM.

[0032]The agents for use in the methods of the invention may be administered as inhibitory compounds in pharmaceutical formulations or as nucleic acid encoding the inhibitors delivered to suitable host cells. The nucleic acid may be directly introduced into a cell in vivo, for example into muscle tissue, or may be first introduced into a cell ex vivo to obtain a cell expressing the inhibitory agent or agents, and the cell then transplanted or grafted into a subject to inhibit or reduce excess accumulation of extracellular matrix.

Problems solved by technology

Dermal scarring following dermal injury results from excessive accumulation of fibrous tissue made up of collagen, fibronectin and proteoglycans at a wound site.

Because the fibrous extracellular matrix lacks elasticity, scar tissue can impair essential tissue function as well as result in an undesirable cosmetic appearance.

Thus, both systems may remain active long after an emergency response has been terminated, which can lead to progressive fibrosis.

The kidney is particularly susceptible to overexpression of TGFβ.

While ACE inhibitors and AII receptor antagonists have been shown to slow the progress of fibrotic diseases, they do not halt disease and TGFβ levels remain somewhat elevated.

Continued activation may result in chronic hypertension and progressive tissue fibrosis leading to organ failure.

Thus, the interactions of RAS and TGFβ production form a complex system which impacts fibrotic ECM accumulation and the incidence of fibrotic disease.

In fibrotic diseases overproduction of TGFβ results in excess accumulation of extracellular matrix which leads to tissue fibrosis and eventually organ failure.

For example, in the kidney, standard diagnostic tests do not provide an abnormal reading until about fifty percent of organ function has been lost.

For example, current therapies for treating fibrotic disease in the kidney are limited to AII blockade using ACE inhibitors such as Enalapril or AII receptor antagonists such as Losartan.

Moreover, it is likely that current therapeutic strategies to reduce TGFβ overproduction may lead to upregulation of other pathways resulting in continued TGFβ overproduction.

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