Galactose-pronged polysaccharides in a formulation for antifibrotic therapies

Abstract

Methods and compositions for reducing fibrosis and cirrhosis are provided in which an effective dose of an admixture of a polysaccharide compound and, for example, a compound selected from the group consisting of antibodies specific to intracellular or cell-surface: (i) beta-PDGF receptors; (ii) synaptophysin; (iii) zvegf3; (iv) CCR1 receptors; (v) connective tissue growth factor; (vi) alpha 1-smooth muscle actin; (vii) matrix metalloproteinases MMP 2 and MMP9; (viii) matrix metalloproteinase inhibitors TIMP1 and TMP2; (ix) integrins; (x) TFG-β1; (xi) endothelin receptor antagonists; and (xii) collagen synthesis and degradation modulating compounds; (xiii) actin synthesis and degradation modulating compounds; and (xiv) tyrosine kinases is administered to an animal in order to treat fibrosis.

What is claimed is: 
     
         1 . A composition comprising an effective amount of a modified galacto-rhamnogalacturonan compound and an acceptable pharmaceutical carrier,
 wherein the modified galacto-rhamnogalacturonan compound is a branched heteropolymer having a backbone of alternating α-1,2 linked rhamnose and α-1,4-linked GalA residues that carries neutral side-chains of predominantly 1,4-β-D-galactose and/or 1,5-α-L-arabinose residues attached to the rhamnose residues of the backbone, and   wherein the galacto-rhamnogalacturonan compound is modified by demethoxylation, deacetylation or depolymerization;   wherein the effective amount of the modified galacto-rhamnogalacturonan, when administered in a subject having at least one of the following: chronic kidney disease associated with the development of fibrosis, established kidney fibrosis, or cirrhosis, is capable of inhibiting or slowing down of the progression of kidney fibrosis or cirrhosis or reduction of established kidney fibrosis or cirrhosis;   wherein the modified galacto-rhamnogalacturonan compound wherein, when the galacto-rhamnogalacturonan compound is utilized to treat LX2 immortalized human hepatic stellate cells in a MTT cell viability assay, the assay treatment results in substantially no decreased viability of activated hepatic stellate cells following administration of the compound.   
     
     
         2 . The composition of  claim 1  wherein the modified galacto-rhamnogalacturonan compound is derived from citrus pectin, apple pectin, soybean hull pectin or sugar beet pectin. 
     
     
         3 . The composition of  claim 1  wherein the modified galacto-rhamnogalacturonan compound is derived from USP pectin. 
     
     
         4 . The composition of  claim 1  wherein the modified galacto-rhamnogalacturonan compound has a molecular weight between 20 kDa and 400 kDa. 
     
     
         5 . The composition of  claim 1  wherein the modified galacto-rhamnogalacturonan compound has a molecular weight between 2 kDa and 200 kDa. 
     
     
         6 . The composition of  claim 1  wherein the ratio of galactose to rhamnose in the modified galacto-rhamnogalacturonan is 3.7 to 1 
     
     
         7 . The composition of  claim 1  wherein the ratio of galactose to rhamnose in the modified galacto-rhamnogalacturonan is between 0.4 to 1 and 6.7 to 1. 
     
     
         8 . The composition of  claim 1  wherein the modified galacto-rhamnogalacturonan further comprises fucose, xylose, mannose or combinations thereof. 
     
     
         9 . The composition of  claim 1  further comprising an antifibrotic compound. 
     
     
         10 . A composition comprising an effective amount of a modified galacto-rhamnogalacturonan compound and an acceptable pharmaceutical carrier,
 wherein the modified galacto-rhamnogalacturonan compound is a branched heteropolymer having a backbone of alternating α-1,2 linked rhamnose and α-1,4-linked GalA residues that carries neutral side-chains of predominantly 1,4-β-D-galactose and/or 1,5-α-L-arabinose residues attached to the rhamnose residues of the backbone, and   wherein the galacto-rhamnogalacturonan compound is modified by demethoxylation, deacetylation or depolymerization;   wherein the effective amount of the modified galacto-rhamnogalacturonan, when administered in a subject having at least one of the following: chronic lung disease associated with the development of fibrosis, established lung fibrosis, or cirrhosis, is capable of inhibiting or slowing down of the progression of lung fibrosis or cirrhosis or reduction of established lung fibrosis or cirrhosis;   wherein the modified galacto-rhamnogalacturonan compound wherein, when the galacto-rhamnogalacturonan compound is utilized to treat LX2 immortalized human hepatic stellate cells in a MTT cell viability assay, the assay treatment results in substantially no decreased viability of activated hepatic stellate cells following administration of the compound.   
     
     
         11 . A method comprising the steps of:
 Obtaining a modified galacto-rhamnogalacturonan compound;   Wherein the modified galacto-rhamnogalacturonan compound is a branched heteropolymer having a backbone of alternating α-1,2 linked rhamnose and α-1,4-linked GalA residues that carries neutral side-chains of predominantly 1,4-β-D-galactose and/or 1,5-α-L-arabinose residues attached to the rhamnose residues of the backbone and wherein the galacto-rhamnogalacturonan compound is modified by demethoxylation, deacetylation or depolymerization; and   Administering parenterally to a subject having at least one of the following disease: chronic kidney disease associated with the development of fibrosis, established kidney fibrosis or cirrhosis, chronic lung disease associated with the development of fibrosis, established lung fibrosis or cirrhosis, an effective dose of the galacto-rhamnogalacturonan compound in an acceptable pharmaceutical carrier that results in at least one of the following:   Inhibition or slowing down of the progression of the fibrosis or cirrhosis or reduction of established fibrosis or cirrhosis; or reduction in the medical consequences of fibrosis or cirrhosis;   wherein, when the galacto-rhamnogalacturonan compound for parenteral administration is utilized to treat LX2 immortalized human hepatic stellate cells in a MTT cell viability assay, the assay treatment results in substantially no decreased viability of activated hepatic stellate cells following administration of the compound.   
     
     
         12 . The method of  claim 11  wherein in the step of obtaining the modified galacto-rhamnogalacturonan compound is obtained from USP pectin. 
     
     
         13 . The method of  claim 11  wherein in the step of obtaining the modified galacto-rhamnogalacturonan compound is obtained from citrus pectin, apple pectin, soybean hull pectin or sugar beet pectin. 
     
     
         14 . The method of  claim 11  wherein in the step of obtaining the modified galacto-rhamnogalacturonan compound has a molecular weight between 20 kDa and 400 kDa. 
     
     
         15 . The method of  claim 11  wherein in the step of obtaining the modified galacto-rhamnogalacturonan compound has a molecular weight between 2 kDa and 200 kDa. 
     
     
         16 . The method of  claim 11  wherein in the step of obtaining the ratio of galactose to rhamnose in the modified galacto-rhamnogalacturonan is 3.7 to 1. 
     
     
         17 . The method of  claim 11  wherein in the step of obtaining the ratio of galactose to rhamnose in the modified galacto-rhamnogalacturonan is between 0.4 to 1 and 6.7 to 1. 
     
     
         18 . The method of  claim 11  wherein in the step of obtaining the modified galacto-rhamnogalacturonan further comprises fucose, xylose, mannose or combinations thereof. 
     
     
         19 . The method of  claim 11  wherein in the step of administering the modified galacto-rhamnogalacturonan is in an admixture with a therapeutic agent. 
     
     
         20 . The method of  claim 19  wherein the therapeutic agent is an antifibrotic compound.