Novel Antagonists for Ameliorating Pulmonary Fibrosis

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$199,467.00
Award Year:
2007
Program:
STTR
Phase:
Phase I
Contract:
1R41HL087463-01
Award Id:
85810
Agency Tracking Number:
HL087463
Solicitation Year:
n/a
Solicitation Topic Code:
n/a
Solicitation Number:
n/a
Small Business Information
AUXAGEN, INC., 7 PRICEWOODS, SAINT LOUIS, MO, 63132
Hubzone Owned:
N
Minority Owned:
N
Woman Owned:
N
Duns:
153650655
Principal Investigator:
JUNG HUANG
(314) 977-9250
HUANGJS@SLU.EDU
Business Contact:
() -
Research Institute:
ST. LOUIS UNIVERSITY

221 N GRAND BLVD
SAINT LOUIS, MO, 63103

Nonprofit college or university
Abstract
DESCRIPTION (provided by applicant): Pulmonary fibrosis, a group of incurable lung diseases with high mortality rates, is characterized by inflammatory cell infiltration, fibroblast proliferation, and excessive deposition of extracellular matrix proteins i n lung parenchyma. Globally, five million people are affected by pulmonary fibrosis. In the U.S. alone, 200,000 suffer from this disease. Of these more than 40,000 die annually, equivalent to the number who die from breast cancer, and forty times more than those who die from cystic fibrosis. The effect of pulmonary fibrosis on quality of life is severe. Currently, there are no effective treatments for pulmonary fibrosis. Hence there is an urgent need to develop therapeutic agents that delay or reverse pulmo nary fibrosis. Accumulating evidence indicates that transforming growth factor-beta (TGF-a) plays an important role in the pathogenesis of pulmonary fibrosis. Studies have shown that antagonizing TGF-a appears to ameliorate lung fibrosis. Therefore TGF-a a ntagonists may serve as important therapeutic agents for pulmonary fibrosis. We recently developed a class of synthetic TGF-a peptide antagonists (termed TGF-a peptantagonists) that antagonize TGF-a activity in cultured cells. Topical application of gel co ntaining TGF-a peptantagonist promotes wound healing and attenuates fibrosis in standard animal skin injury models. However, the use of TGF-a peptantagonists for treating pulmonary fibrosis is limited by its poor solubility in aqueous solution at neutral p H. The goal of this proposal is to develop novel TGF-a peptantagonist derivatives with increased solubility, long plasma half-life, and potent antagonist activity. These agents should be effective for treating pulmonary fibrosis by inhalation and intraveno us routes. Preliminary studies indicate that a high-molecular-weight TGF-a peptantagonist derivative we have recently developed that has excellent solubility and potent antagonist activity, effectively ameliorates bleomycin-induced lung fibrosis in mice. T hese results suggest that TGF-a antagonism may be a viable therapeutic strategy. In this proposal there are two specific aims: 1) to generate higher-molecular-weight derivatives of TGF-a peptantagonists with potent antagonist activity. The methodologies wi ll include chemical synthesis, biochemical, cell biological and plasma clearance assays and 2) to determine the therapeutic effects of higher-molecular-weight derivatives of TGF-a peptantagonist on bleomycin-induced pulmonary fibrosis in mice. The methodol ogies will include biochemical, histological and semi-quantitative histopathological analyses. The new forms of TGF-a peptantagonist developed in these studies should be ideal drug candidates for treating pulmonary fibrosis in humans. The goal of this proj ect is to develop therapeutic agents for pulmonary fibrosis which currently lacks effective treatments. The novel antagonists developed in this project should be ideal drug candidates for treating pulmonary fibrosis in humans.

* information listed above is at the time of submission.

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