Compounds and Methods for the Treatment of Inflammatory Diseases of the CNS

Abstract

Inflammatory diseases in the CNS can be treated or alleviated by the administration of an oligonucleotide in an amount sufficient to reduce the influx of mononuclear cells to the central nervous system by down-regulating the expression of at least one cell surface marker. For example multiple sclerosis can be treated or at least alleviated, by the administration of an oligonucleotide in a dose effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system. The oligonucleotide can be used alone, or in combination with other treatment strategies.

1 . A method for the treatment and/or alleviation of multiple sclerosis in a multiple sclerosis patient in need thereof, the method comprising administering an oligonucleotide to the patient in an amount effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system by down-regulating the expression of at least one specific cell surface marker, wherein the oligonucleotide is an isolated and substantially purified oligonucleotide selected from the group consisting of SEQ ID NO: 9 (IDX0150), and SEQ ID NO: 10 (IDX0980), and wherein the administration of the oligonucleotide is made in the absence of corticosteroid administration. 
     
     
         2 . The method according to  claim 1 , wherein the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         3 . The method according to  claim 1 , wherein the oligonucleotide is SEQ ID NO: 10 (IDX0980). 
     
     
         4 . The method according to  claim 1 , wherein the cell surface marker is at least one of CD49d, CXCR3 (CD183), CCR2 (CD192), and CCRS (CD195). 
     
     
         5 . The method of  claim 4 , wherein the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         6 . The method of  claim 4 , wherein the cell surface marker is CD49d and the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         7 . The method according to  claim 1 , wherein the route of administration is chosen from mucosal, subcutaneous, intramuscular, intravenous and intraperitoneal administration. 
     
     
         8 . The method according to  claim 7 , wherein the mucosal administration is chosen from nasal, oral, gastric, ocular, rectal, urogenital and vaginal administration. 
     
     
         9 . The method according to  claim 7 , wherein the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         10 . The method according to  claim 8 , wherein the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         11 . A method for the treatment and/or alleviation of multiple sclerosis in a multiple sclerosis patient in need thereof, the method comprising administering an oligonucleotide to the patient in an amount effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system by reducing the production of VEGF, wherein the oligonucleotide is an isolated and substantially purified oligonucleotide selected from the group consisting of SEQ ID NO: 9 (IDX0150), and SEQ ID NO: 10 (IDX0980), and wherein the administration of the oligonucleotide is made in the absence of corticosteroid administration. 
     
     
         12 . The method according to  claim 11 , wherein the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         13 . The method according to  claim 11 , wherein the oligonucleotide is SEQ ID NO:
 10 (IDX0980).   
     
     
         14 . The method according to  claim 11 , wherein the route of administration is chosen from mucosal, subcutaneous, intramuscular, intravenous and intraperitoneal administration. 
     
     
         15 . The method according to  claim 14 , wherein the mucosal administration is chosen from nasal, oral, gastric, ocular, rectal, urogenital and vaginal administration. 
     
     
         16 . The method according to  claim 14 , wherein the oligonucleotide is SEQ ID NO: 9 (IDX0150). 
     
     
         17 . A method for the treatment and/or alleviation of multiple sclerosis in a multiple sclerosis patient in need thereof by inhibiting or reducing the influx of mononuclear and/or autoaggressive cells to the central nervous system by down-regulating the expression of at least one specific cell surface marker, the method comprising administering an oligonucleotide to the patient in an amount effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system by down-regulating the expression of at least one specific cell surface marker, wherein the oligonucleotide is the isolated oligonucleotide G*G*GGGACGATCGTCG*G*G*G*G*G (SEQ ID NO: 10) (IDX0980), wherein * represents phosphorothioate modification. 
     
     
         18 . A method for the treatment and/or alleviation of multiple sclerosis in a multiple sclerosis patient in need thereof by inhibiting or reducing the influx of mononuclear and/or autoaggressive cells to the central nervous system by reducing the production of VEGF, the method comprising administering an oligonucleotide to the patient in an amount effective to inhibit or reduce the influx of mononuclear and/or autoaggressive cells to the central nervous system by reducing the production of VEGF, wherein the oligonucleotide is an isolated oligonucleotide of the nucleotide sequence G*G*GGGACGATCGTCG*G*G*G*G*G (SEQ ID NO: 10) (IDX0980), wherein * represents phosphorothioate modification, and wherein the oligonucleotide is administered in a pharmaceutical composition comprising a pharmacologically compatible and physiologically acceptable excipient or carrier. 
     
     
         19 . The method according to  claim 18 , wherein the route of administration is chosen from mucosal, subcutaneous, intramuscular, intravenous and intraperitoneal administration. 
     
     
         20 . The method according to  claim 19 , wherein the mucosal administration is chosen from nasal, oral, gastric, ocular, rectal, urogenital and vaginal administration. 
     
     
         21 . The method according to  claim 18 , wherein the pharmacologically compatible and physiologically acceptable excipient or carrier is selected from the group consisting of saline, liposomes, surfactants, mucoadhesive compounds, enzyme inhibitors, bile salts, absorption enhancers, cyclodextrins, and a combination thereof 
     
     
         22 . The method according to  claim 18 , wherein the oligonucleotide is administered in an amount of about 1 to about 2000 μg per kg body weight. 
     
     
         23 . The method according to  claim 18 , wherein the oligonucleotide is administered in an amount of about 1 to about 1000 μg per kg body weight. 
     
     
         24 . The method according to  claim 18 , wherein the oligonucleotide is administered in an amount of about 1 to 500 μg per kg body weight.