Methods for increasing intracellular activity of hsp70

Abstract

The present invention relates to a bioactive agent capable of increasing the intracellular concentration and/or activity of Hsp70 for use in the treatment of a lysosomal storage disease which arise from a defect in an enzyme whose activity is not directly associated with the presence of lysosomal BMP as a co-factor; such as glycogen storage diseases, gangliosidoses, neuronal ceroid lipofuscinoses, cerebrotendinous cholesterosis, Wolman's disease, cholesteryl ester storage disease, disorders of glycosaminoglycan metabolism, mucopolysaccharidoses, disorders of glycoprotein metabolism, mucolipidoses, aspartylglucosaminuria, fucosidosis, mannosidoses, and sialidosis type II.

1 . A method of treatment of a lysosomal storage disease selected from the group consisting of glycogen storage diseases, gangliosidoses, lysosomal cholesterol storage diseases, disorders of glycosaminoglycan metabolism, mucopolysaccharidoses, disorders of glycoprotein metabolism, mucolipidoses, aspartylglucosaminuria, fucosidosis, mannosidoses, sialidosis type II, and neuronal ceroid lipofuscinoses,
 said method comprising administering to an individual in need thereof a bioactive agent capable of increasing the intracellular concentration of Hsp70, wherein said bioactive agent is selected from the group consisting of a hydroxylamine derivative capable of amplifying Hsp70 gene expression; Hsp70; and a functional fragment or variant of Hsp70 having at least 95% sequence identity to Hsp70.   
     
     
         2 . The method according to  claim 1 , wherein said disease is a glycogen storage disease selected from the group consisting of cardiac glycogenosis, Andersen disease, Cori disease (Forbes disease), Hers disease, McArdle disease, Pompe disease, Tauri disease (Tarui disease), and von Gierke disease. 
     
     
         3 . The method according to  claim 1 , wherein said disease is a gangliosidosis selected from the group consisting of Sandhoff disease (or GM2 gangliosidosis type II), classic infantile Sandhoff disease, juvenile Sandhoff disease, adult/late onset Sandhoff disease, Tay-Sachs disease (or GM2 gangliosidosis type I), infantile Tay-Sachs disease, juvenile Tay-Sachs disease, adult/late onset Tay-Sachs disease, GM2-gangliosidosis AB variant, GM1 gangliosidosis, early infantile GM1 gangliosidosis, late infantile GM1 gangliosidosis, adult GM1 gangliosidosis, GM3 gangliosidosis, and Mucolipidosis IV. 
     
     
         4 . The method according to  claim 1 , wherein said lysosomal cholesterol storage disease is selected from the group consisting of cerebrotendinous cholesterosis, Wolman's disease and cholesteryl ester storage disease. 
     
     
         5 . The method according to  claim 1 , wherein said disease is a mucopolysaccharidosis selected from the group consisting of a type I mucopolysaccharidosis, a type II mucopolysaccharidosis, a type III mucopolysaccharidosis, a type IV mucopolysaccharidosis, a type VI mucopolysaccharidosis, a type VII mucopolysaccharidosis, a type VIII mucopolysaccharidosis, and a type IX mucopolysaccharidosis. 
     
     
         6 . The method according to  claim 1 , wherein said mucopolysaccharidosis is selected from the group consisting of Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Hunter's syndrome, DiFerrante syndrome, Maroteaux-Lamy syndrome (mild or severe), Morquio syndrome (classic or Morquio-like), and Sanfilippo syndrome (type A, B, C, or D). 
     
     
         7 . The method according to  claim 1 , wherein said disease is a mucolipidosis selected from the group consisting of mucolipidosis II (I-cell disease) and mucolipidosis III (pseudo-Hurler polydystrophy). 
     
     
         8 . The method according to  claim 1 , wherein said disease is a disorder of glycoprotein metabolism selected from the group consisting of aspartylglucosaminuria, fucosidosis, mannosidosis, alpha-mannosidosis, alpha-mannosidosis type I, alpha-mannosidosis type II, beta-mannosidosis, and sialidosis type II (mucolipidosis I). 
     
     
         9 . The method according to  claim 1 , wherein said disease is a neuronal ceroid lipofuscinosis selected from the group consisting of Batten disease (Spielmeyer-Vogt disease), Bielschowsky-Jansky disease, Kufs disease, and Santavuori-Haltia disease. 
     
     
         10 . The method according to  claim 1 , wherein said bioactive agent is administered in combination with at least one other treatment modality. 
     
     
         11 . The method according to  claim 10 , wherein said at least one other treatment modality is selected from the group consisting of enzyme replacement therapy (ERT), pain relievers, corticosteroids, substrate reduction therapy, a transplantation and physical therapy. 
     
     
         12 . The method according to  claim 1 , wherein said hydroxylamine derivative is selected from the group consisting of arimoclomol, BRX-220, BRX-345, iroxanadine, bimoclomol and BGP-15. 
     
     
         13 . The method according to  claim 1 , wherein said hydroxylamine derivative is selected from the group consisting of arimoclomol, BRX-220 and BRX-345. 
     
     
         14 . The method according to  claim 1 , wherein said hydroxylamine derivative is iroxanadine. 
     
     
         15 . The method according to  claim 1 , wherein said Hsp70 is derived from a mammal selected from the group consisting of human ( Homo sapiens ), mouse ( Mus musculus ), cow, dog, rat, ferret, pig, sheep, and monkey. 
     
     
         16 . The method according to  claim 1 , wherein said bioactive agent is Hsp70. 
     
     
         17 . The method according to  claim 1 , wherein said bioactive agent is recombinant Hsp70 (rHsp70). 
     
     
         18 . The method according to  claim 1 , wherein said bioactive agent is a functional fragment or variant of Hsp70 having at least 95% sequence identity to Hsp70. 
     
     
         19 . The method according to  claim 1 , wherein said functional fragment or variant of Hsp70 having at least 95% sequence identity to Hsp70 comprises all or part of the ATPase domain of Hsp70; and/or comprises tryptophan at amino acid position 90 of the Hsp70 ATPase domain. 
     
     
         20 . The method according to  claim 1 , wherein administering said Hsp70 or said functional fragment or variant of Hsp70 having at least 95% sequence identity to Hsp70 comprises administering an expression vector encoding said Hsp70 or said functional fragment or variant of Hsp70 having at least 95% sequence identity to Hsp70.