Galactose-pronged carbohydrate compounds for the treatment of diabetic nephropathy and associated disorders

1. A method comprising:

a. obtaining a composition for parenteral or enteral administration comprising a galacto-rhamnogalacturonate in a pharmaceutical acceptable carrier, and

b. administering to a subject in need thereof an effective dose of the composition that results in at least one of the following:

at least a 10% reduction in proteinuria or at least a 10% reduction in the rate of increase of proteinuria;

at least a 10% increase in glomerular filtration rate or at least a 10% reduction in the rate of decline of glomerular filtration rate;

at least a 10% reduction of mesangial extracellular matrix or at least a 10% reduction in the rate of increase of mesangial extracellular matrix;

at least a 5% reduction in the glomerular capillary basement membrane thickness;

at least a 10% reduction in the fractional volume of the mesangium or at least a 10% reduction in the rate of increase of the fractional volume of the mesangium;

at least a 10% reduction in the interstitial tubular volume or at least a 10% reduction in the rate of increase in the interstitial tubular volume;

at least a 10% reduction in the amount of collagen in the interstitial tubular space or at least a 10% reduction in the rate of increase of the collagen in the interstitial tubular space;

at least 10% change in the level of the serum biomarkers of diabetic nephropathy;

wherein the subject in need thereof has at least one of the following: a primary glomerulopathic disease, a secondary glomerulopathic disease, and renal tubule-interstitial disorder, and

wherein the effective dose is equivalent to an animal dose of 0.1 mg/kg to 9.99 mg/kg.

2. The method of claim 1 wherein the galacto-rhamnogalacturonate comprises a 1,4-linked galacturonic acid (GalA) and methyl galacturonate (MeGalA) residues backbone linked to branched heteropolymers of alternating oligomers of α-1,2linked rhamnose and α-1,4-linked GalA residues, the rhamnose residues carrying a primary branching of oligomers of 1,4-β-D-galactose residues.

3. The method of claim 1 wherein the galacto-rhamnogalacturonate comprises a 1,4-linked galacturonic acid (GalA) residues backbone linked to branched heteropolymers of alternating oligomers of α-1,2 linked rhamnose and α-1,4-linked GalA residues, the rhamnose residues carrying a primary branching of oligomers of 1,4-β-D-galactose residues.

4. The method of claim 1 wherein the galacto-rhamnogalacturonate further comprises xylose, glucose, fucose residues or combination thereof.

5. The method of claim 1 wherein the galacto-rhamnogalacturonate has an average molecular weight distribution of 2,000 to 80,000, 20,000 to 70,000, or 5,000 to 55,000 Daltons, as determined by SEC-RI and/or the SEC-MALLS methods.

6. The method of claim 1 wherein the galacto-rhamnogalacturonate is substantially free of 1,5-α-L-Ara residues.

7. The method of claim 1 wherein the serum biomarkers of diabetic nephropathy comprise inflammatory and hemodynamic cytokines, TNF-alpha, TGF-beta or IL-8, osteopontin, or a metabolic profile of serum components indicative of diabetic nephropathy presence or severity.

8. The method of claim 1 wherein the composition further comprises one or more galectin inhibitors.

9. The method of claim 8 wherein the galectin inhibitors comprise small organic inhibitors of galectin, monoclonal antibodies, RNA inhibitors, small binding peptides, protein inhibitors or combinations thereof.

10. The method of claim 1 wherein the effective dose ranges from 0.05 to 0.49 mg/kg.

11. A method comprising:

a. obtaining a composition for parenteral or enteral administration comprising a galactoarabino-rhamnogalacturonate in a pharmaceutical acceptable carrier, and

b. administering to a subject in need thereof an effective dose of the composition that results in at least one of the following:

at least a 10% reduction in proteinuria or at least a 10% reduction in the rate of increase of proteinuria;

at least a 10% increase in glomerular filtration rate or at least a 10% reduction in the rate of decline of glomerular filtration rate;

at least a 10% reduction of mesangial extracellular matrix or at least a 10% reduction in the rate of increase of mesangial extracellular matrix;

at least a 5% reduction in the glomerular capillary basement membrane thickness;

at least a 10% reduction in the fractional volume of the mesangium or at least a 10% reduction in the rate of increase of the fractional volume of the mesangium;

at least a 10% reduction in the interstitial tubular volume or at least a 10% reduction in the rate of increase in the interstitial tubular volume;

at least a 10% reduction in the amount of collagen in the interstitial tubular space or at least a 10% reduction in the rate of increase of the collagen in the interstitial tubular space;

at least 10% change in the level of the serum biomarkers of diabetic nephropathy;

wherein the subject in need thereof has at least one of the following: a primary glomerulopathic disease, a secondary glomerulopathic disease, and renal tubule-interstitial disorder, and

wherein the effective dose is equivalent to an animal dose of 0.1 mg/kg to 1.99 mg/kg.

12. The method of claim 11 wherein the galactoarabino-rhamnogalacturonate comprises a 1,4-linked galacturonic acid (GalA) and methyl galacturonate (MeGalA) residues backbone linked to branched heteropolymers of alternating oligomers of α-1,2 linked rhamnose and α-1,4-linked GalA residues, the rhamnose residues carrying a primary branching of oligomers of 1,4-β-D-galactose residues, 1,5-α-L-arabinose residues, or combinations thereof.

13. The method of claim 11 wherein the molar percent of the 1,4-β-D-Gal, 1,5-α-L-Ara residues and combination thereof is at least 8% of the total molar carbohydrates.

14. The method of claim 11 wherein the 1,4-β-D-Gal and 1,5-α-L-Ara residues are present at a ratio ranging from 1:1 to 3:1.

15. The method of claim 11 wherein the galactoarabino-rhamnogalacturonate has an average molecular weight distribution of 2,000 to 80,000, 20,000 to 70,000, or 5,000 to 55,000 Daltons, as determined by SEC-RI and/or the SEC-MALLS methods.

16. The method of claim 11 wherein the galactoarabino-rhamnogalacturonate has a degree of methoxylation ranging from 40% to 70%.

17. The method of claim 11 wherein the galactoarabino-rhamnogalacturonate has a methyl galacturonate plus galacturonic acid ratio to galactose ranging from 4:1 to 7:1.

18. The method of claim 12 wherein the effective dose ranges from 0.05 to 0.19 mg/kg.