Gene regulation therapy involving ferritin

Abstract

A method is described for regulating gene expression related to iron metabolism to ameliorate diseases that include sickle cell disease, cancers, neurodegenerative diseases, Friedreich's ataxia and other neuromuscular disorders, and atherosclerosis. This approach is illustrated by recent findings that show that ferritin-H, an iron-binding protein that is present in cell nuclei, can repress the human β-globin gene, the gene that is mutated in sickle cell disease. Increased expression of ferritin-H or a related ferritin-family peptide, given to effected cells either as the peptide itself (or a part thereof), as an expression clone of the ferritin-H-subfamily gene, or via a gene regulator that increases expression of the ferritin-H-subfamily gene itself, prevents or ameliorates expression of the disease state in disorders where increased availability of iron is implicated in the etiology of the disease, including those named above.

1 . A method for suppressing disease caused or enhanced by effects of intracellular iron mismanagement comprising: 
 increasing the intracellular amount of at least one ferritin-H or a derivative thereof to an effective level.    
     
     
         2 . The method for suppressing disease of  claim 1  wherein exogenous ferritin-H or derivative thereof is introduced into globin-producing cells.  
     
     
         3 . The method for suppressing disease of  claim 1  wherein the globin-producing cells are fused with liposomal constructs containing ferritin-H or derivative thereof.  
     
     
         4 . The method for suppressing disease of  claim 1  wherein the ferritin-H or derivative thereof is produced by inducing expression of an endogenous ferritin gene of the globin-producing cell.  
     
     
         5 . The method for suppressing disease of  claim 1  wherein the intracellular concentration ferritin-H or a derivative thereof is elevated by repressing expression of Ferritin-L or a derivative thereof.  
     
     
         6 . The method for suppressing disease of  claim 1  wherein the expression of ferritin-L or a derivative thereof is repressed by introduction into the cell of antisense DNA specific to the ferritin-L or derivative thereof.  
     
     
         7 . The method for suppressing disease of  claim 1  wherein the ferritin-H or derivative thereof is produced after transfection of at least one cell with a vector encoding ferritin-H or a derivative thereof.  
     
     
         8 . The method for suppressing disease of  claim 7  wherein the transfection occurs in vivo.  
     
     
         9 . The method for suppressing disease of  claim 7  wherein the transfection occurs ex vivo.  
     
     
         10 . The method for suppressing disease of  claim 7  wherein the transfection comprises inserting the vector into a liposomal construct having a ligand or antibody on the surface of the construct that is capable of binding to a specific receptor on the surface of a cell.  
     
     
         11 . A method for treating sickle cell disease comprising: suppressing the expression of adult β-globin genes in globin-producing cells with ferritin-H or a derivative thereof.  
     
     
         12 . The method for treating sickle cell disease of  claim 11  wherein exogenous ferritin-H or a derivative thereof is introduced into globin-producing cells.  
     
     
         13 . The method for treating sickle cell disease of  claim 12  wherein the globin-producing cells are fused with liposomal constructs containing ferritin-H or a derivative thereof.  
     
     
         14 . The method for treating sickle cell disease of  claim 11  wherein the ferritin-H or derivative thereof is produced by inducing expression of an endogenous ferritin gene of the globin-producing cell.  
     
     
         15 . The method for treating sickle cell disease of  claim 11  wherein the intracellular concentration ferritin-H or a derivative thereof is elevated by repressing expression of Ferritin-L or a derivative thereof.  
     
     
         16 . The method for treating sickle cell disease of  claim 15  wherein the expression of L or a derivative thereof is repressed by introduction into the cell of antisense DNA specific to the ferritin-L or derivative thereof.  
     
     
         17 . The method for treating sickle cell disease of  claim 11  wherein the ferritin-H or derivative thereof is produced after transfection of at least one cell with a vector encoding ferritin-H or a derivative thereof.  
     
     
         18 . The method for treating sickle cell disease of  claim 17  wherein the transfection comprises inserting the vector into a liposomal construct having a ligand or antibody on the surface of the construct that is capable of binding to a specific receptor on the surface of a cell.  
     
     
         19 . The method for treating sickle cell disease of  claim 11  wherein the ferritin-H or derivative thereof binds to the promoter region of the β-globin gene.  
     
     
         20 . A method for treating sickle cell disease comprising: administering to a patient a ferritin-containing vehicle in a pharmaceutically acceptable carrier, said vehicle targeting hematopoietic stem cells, erythroid precursor cells or, hematopoietic cells.  
     
     
         21 . A method for treating neurological disorders caused or enhanced by excess intracellular iron, the method comprising: increasing the intracellular amount of ferritin-H or a derivative thereof in affected neural cells to an effective level.  
     
     
         22 . A pharmaceutical composition comprising: ferritin-H or a derivative thereof; and, a cell specific targeting ligand.  
     
     
         23 . A pharmaceutical composition comprising: a gene encoding ferritin-H or a derivative thereof; and, a suitable transfection vector.