Compositions and methods for the treatment of juvenile neuronal ceroid lipofuscinosis and related disorders

Abstract

Provided are materials and methods for the prevention and treatment of Juvenile Neuronal Ceroid Lipofuscinosis comprising administration of an effective amount of at least one of a hemi-channel inhibitor or a phosphodiesterase-4 inhibitor. In some embodiments, the methods comprise administration of an effective amount of each of a hemi-channel inhibitor and a phosphodiesterase-4 inhibitor. Also provided are pharmaceutical compositions comprising a hemi-channel inhibitor or a phosphodiesterase-4 inhibitor, as well as kits comprising at least one effective dose of a hemi-channel inhibitor or a phosphodiesterase-4 inhibitor or a combination of both.

What is claimed is: 
     
         1 . A method of reducing the rate of development of Juvenile Neuronal Ceroid Lipofuscinosis comprising administering an effective amount of a hemi-channel inhibitor or a phosphodiesterase-4 inhibitor to a subject. 
     
     
         2 . The method according to  claim 1  wherein the hemi-channel inhibitor is selected from the group consisting of INI-0602, glycyrrhizic acid, 18α-glycyrrhetinic acid, carbenoxolone, a carbenoxolone derivative, a carbenoxolone analog, a fenamate, flufenemic acid, a flufenemic acid derivative, a flufenemic acid analog, heptanol, octanol, arachidonic acid, quinine, a quinine derivative, a connexin (Cx) fragment, a connexin mimetic peptide, a connexin inhibitor, an anti-connexin antibody, a connexin expression modulator, a lysophosphatidic acid, an inhibitor of arachidonic acid metabolism, niflumic acid, 5-nitro-2(3-phenylpropylamino)benzoic acid and a heavy metal. 
     
     
         3 . The method according to  claim 2  wherein the connexin fragment is a fragment of Connexin 43 or Connexin 30. 
     
     
         4 . The method according to  claim 2  wherein the connexin mimetic peptide is Gap26 or Gap27. 
     
     
         5 . The method according to  claim 2  wherein the connexin expression modulator is siRNA, shRNA, miRNA, Nexagon®, Peptagon™, Protein Kinase C or Src. 
     
     
         6 . The method according to  claim 2  wherein the hemi-channel inhibitor is INI-0602. 
     
     
         7 . The method according to  claim 1  wherein the phosphodiesterase-4 inhibitor is selected from the group consisting of propentofylline, apremilast, cilomilast, diazepam, drotaverine, etazolate, filaminast, glaucine, HT-0712, ibudilast, luteolin, mesembrine, mesembrenone, pentoxifylline, piclamilast, rolipram, roflumilast, ronomilast, RPL-554, GSK256066, chlorbipram, MK-0952, MK-0359, MK-0873, KCA-1490, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide and thalidomide. 
     
     
         8 . The method according to  claim 1  wherein an effective amount of a hemi-channel inhibitor and an effective amount of a phosphodiesterase-4 inhibitor are administered to a subject. 
     
     
         9 . A method of treating Juvenile Neuronal Ceroid Lipofuscinosis comprising administering an effective amount of a hemi-channel inhibitor or a phosphodiesterase-4 inhibitor to a subject. 
     
     
         10 . The method according to  claim 9  wherein the hemi-channel inhibitor is selected from the group consisting of INI-0602, glycyrrhizic acid, 18α-glycyrrhetinic acid, carbenoxolone, a carbenoxolone derivative, a carbenoxolone analog, a fenamate, flufenemic acid, a flufenemic acid derivative, a flufenemic acid analog, heptanol, octanol, arachidonic acid, quinine, a quinine derivative, a connexin (Cx) fragment, a connexin mimetic peptide, a connexin inhibitor, an anti-connexin antibody, a connexin expression modulator, a lysophosphatidic acid, an inhibitor of arachidonic acid metabolism, niflumic acid, 5-nitro-2(3-phenylpropylamino)benzoic acid and a heavy metal. 
     
     
         11 . The method according to  claim 9  wherein the phosphodiesterase-4 inhibitor is selected from the group consisting of propentofylline, apremilast, cilomilast, diazepam, drotaverine, etazolate, filaminast, glaucine, HT-0712, ibudilast, luteolin, mesembrine, mesembrenone, pentoxifylline, piclamilast, rolipram, roflumilast, ronomilast, RPL-554, GSK256066, chlorbipram, MK-0952, MK-0359, MK-0873, KCA-1490, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide and thalidomide. 
     
     
         12 . The method according to  claim 9  wherein an effective amount of a hemi-channel inhibitor and an effective amount of a phosphodiesterase-4 inhibitor are administered to a subject. 
     
     
         13 . A pharmaceutical composition for reducing the development of Juvenile Neuronal Ceroid Lipofuscinosis comprising at least one effective dose of a hemi-channel inhibitor and at least one effective dose of a phosphodiesterase-4 inhibitor. 
     
     
         14 . The pharmaceutical composition according to  claim 13  wherein the hemi-channel inhibitor is selected from the group consisting of INI-0602, glycyrrhizic acid, 18α-glycyrrhetinic acid, carbenoxolone, a carbenoxolone derivative, a carbenoxolone analog, a fenamate, flufenemic acid, a flufenemic acid derivative, a flufenemic acid analog, heptanol, octanol, arachidonic acid, quinine, a quinine derivative, a connexin (Cx) fragment, a connexin mimetic peptide, a connexin inhibitor, an anti-connexin antibody, a connexin expression modulator, a lysophosphatidic acid, an inhibitor of arachidonic acid metabolism, niflumic acid, 5-nitro-2(3-phenylpropylamino)benzoic acid and a heavy metal. 
     
     
         15 . The pharmaceutical composition according to  claim 13  wherein the quinine derivative is mefloquine. 
     
     
         16 . The pharmaceutical composition according to  claim 13  wherein the connexin fragment comprises an extracellular domain of a connexin. 
     
     
         17 . The pharmaceutical composition according to  claim 13  wherein the connexin fragment is a fragment of Connexin 43 or Connexin 30. 
     
     
         18 . The pharmaceutical composition according to  claim 13  wherein the connexin mimetic peptide is Gap26 or Gap27. 
     
     
         19 . The pharmaceutical composition according to  claim 13  wherein the connexin expression modulator is siRNA, shRNA, miRNA, Nexagon®, Peptagon™, Protein Kinase C or Src. 
     
     
         20 . The pharmaceutical composition according to  claim 13  wherein the phosphodiesterase-4 inhibitor is selected from the group consisting of propentofylline, apremilast, cilomilast, diazepam, drotaverine, etazolate, filaminast, glaucine, HT-0712, ibudilast, luteolin, mesembrine, mesembrenone, pentoxifylline, piclamilast, rolipram, roflumilast, ronomilast, RPL-554, GSK256066, chlorbipram, MK-0952, MK-0359, MK-0873, KCA-1490, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide, and thalidomide.