Hsp therapy in conjunction with a low antigenicity diet

Abstract

The present invention relates to a method for suppression, prevention, delaying the onset or treatment of diabetes, by administering to an individual in need thereof a fragment of Hsp60 or analog thereof in conjunction with a low antigenicity diet. The invention is exemplified using DiaPep277™, an analog of residues 437-460 of human Hsp60 in combination with a hydrolyzed casein diet.

1 . A method for suppression, prevention, delaying the onset or treatment of diabetes, comprising administering to an individual in need thereof a fragment of Hsp60 or analog thereof in conjunction with a low antigenicity diet. 
     
     
         2 . The method according to  claim 1  wherein a diabetogenic protein is omitted from the diet or replaced with a hydrolyzed or denatured form of the diabetogenic protein. 
     
     
         3 . The method according to  claim 2  wherein the diabetogenic protein is selected from the group consisting of: casein, lactoglobulin, albumin, (pro)insulin, wheat gluten, soy bean proteins, and heat shock proteins. 
     
     
         4 . The method according to  claim 1  wherein the diet comprises hydrolyzed or denatured protein. 
     
     
         5 . The method according to  claim 4  wherein the hydrolyzed protein is selected from the group consisting of: casein hydrolysate, whey hydrolysate, soy hydrolysate, or a mixture thereof. 
     
     
         6 . The method according to  claim 4  wherein the hydrolyzed protein is hydrolyzed casein. 
     
     
         7 . The method according to  claim 1  wherein the protein source of the diet is replaced with free amino acids, short-chain peptides, or mixtures thereof. 
     
     
         8 . The method according to  claim 1  wherein the diabetes is type 1 diabetes. 
     
     
         9 . The method according to  claim 1  wherein the diabetes is latent autoimmune diabetes in adults (LADA). 
     
     
         10 . The method of  claim 1  wherein the hsp60 fragment comprises residues 437-460 having the sequence Val-Leu-Gly-Gly-Gly-Cys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-AspSer-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO: 1), or a salt or functional derivative thereof. 
     
     
         11 . The method of  claim 1  wherein the analog of hsp60 comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-AspSer-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2), or a salt or functional derivative thereof. 
     
     
         12 . The method of  claim 1  wherein the hsp60 fragment or analog comprises a sequence selected from the group consisting of: residues 31-50 of human Hsp60: Lys-PheGly-Ala-Asp-Ala-Arg-Ala-Leu-Met-Leu-Gln-Gly-Val-Asp-Leu-Leu-Ala-Asp-Ala (SEQ ID NO:3); residues 136-155 of human Hsp60: Asn-Pro-Val-Glu-Ile-Arg-Arg-Gly-Val-Met-LeuAla-Val-Asp-Ala-Val-Ile-Ala-Glu-Leu (SEQ ID NO:4); residues 151-170 of human Hsp60: Val-Ile-Ala-Glu-Leu-Lys-Lys-Gln-Ser-Lys-Pro-Val-Thr-Thr-Pro-Glu-Glu-Ile-Ala-Gln (SEQ ID NO:5); residues 166-185 of human Hsp60: Glu-Glu-Ile-Ala-Gln-Val-Ala-Thr-Ile-Ser-Ala-Asn-Gly-Asp-Lys-Glu-Ile-Gly-Asn-Ile (SEQ ID NO:6); residues 195-214 of human Hsp60: Arg-Lys-Gly-Val-Ile-Thr-Val-Lys-Asp-Gly-Lys-Thr-Leu-Asn-Asp-Glu-Leu-Glu-Ile-Ile (SEQ ID NO:7); residues 255-274 of human Hsp60: Gln-Ser-Ile-Val-Pro-Ala-Leu-Glu-Ile-Ala-AsnAla-His-Arg-Lys-Pro-Leu-Val-Ile-Ile (SEQ ID NO:8); residues 286-305 of human Hsp60: Leu-Val-Leu-Asn-Arg-Leu-Lys-Val-Gly-Leu-Gln-Val-Val-Ala-Val-Lys-Ala-Pro-Gly-Phe (SEQ ID NO:9); residues 346-365 of human Hsp60: Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-AspAla-Met-Leu-Leu-Lys-Gly-Lys-Gly-Asp-Lys-Ala (SEQ ID NO: 10); residues 421-440 of human Hsp60: Val-Thr-Asp-Ala-Leu-Asn-Ala-Thr-Arg-Ala-Ala-Val-Glu-Glu-Gly-Ile-Val-Leu-Gly-Gly (SEQ ID NO:11); residues 436-455 of human Hsp60: Ile-Val-Leu-Gly-Gly-GlyCys-Ala-Leu-Leu-Arg-Cys-Ile-Pro-Ala-Leu-Asp-Ser-Leu-Thr (SEQ ID NO:12); residues 466-485 of human Hsp60: Glu-Ile-Ile-Lys-Arg-Thr-Leu-Lys-Ile-Pro-Ala-Met-Thr-Ile-Ala-LysAsn-Ala-Gly-Val (SEQ ID NO: 13); residues 511-530 of human Hsp60: Val-Asn-Met-Val-Glu-Lys-Gly-Ile-Ile-Asp-Pro-Thr-Lys-Val-Val-Arg-Thr-Ala-Leu-Leu (SEQ ID NO: 14); residues 343-366 of human Hsp60: Gly-Lys-Val-Gly-Glu-Val-Ile-Val-Thr-Lys-Asp-Asp-Ala-Met (SEQ ID NO: 15); or a salt or functional derivative thereof. 
     
     
         13 . The method of  claim 1  wherein the Hsp60 fragment or analog is administered by a route of administration selected from oral, nasal, bronchial, topical, transdermal and systemic administration. 
     
     
         14 . The method of  claim 1  wherein the Hsp60 fragment or analog is administered orally. 
     
     
         15 . The method of  claim 14  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.02 mg/kg to about 10 mg/kg. 
     
     
         16 . The method according to  claim 15  wherein the Hsp60 fragment or analog is administered in a dosage ranging from about 0.05 mg/kg to about 2 mg/kg. 
     
     
         17 . The method of  claim 1  wherein the Hsp60 fragment or analog is formulated for oral administration. 
     
     
         18 . The method of  claim 1  wherein insulitis is inhibited. 
     
     
         19 . The method for delaying the onset of diabetes according to  claim 1  wherein the diabetes is type 1 diabetes and the diet comprises hydrolyzed casein diet. 
     
     
         20 . The method of  claim 19  wherein the analog of hsp60 comprises DiaPep277 having the sequence: Val-Leu-Gly-Gly-Gly-Val-Ala-Leu-Leu-Arg-Val-Ile-Pro-Ala-Leu-AspSer-Leu-Thr-Pro-Ala-Asn-Glu-Asp (SEQ ID NO:2), or a salt or functional derivative thereof.