Methods and compositions for treating disorders associated with cortico-hippocampal hyperactivity

Abstract

A pharmaceutical composition includes an active agent capable of reducing dihydroorotate dehydrogenase (DHODH) enzyme activity in the central nervous system (CNS), and a pyrimidine nucleobase or an intermediate in the de novo synthesis thereof. A method for treating a disease or disorder associated with cortico-hippocampal hyperactivity in a subject in need thereof, or for preventing or delaying onset of the disease or disorder in a subject diagnosed as suffering from an elevated cortico-hippocampal activity or being at genetic risk for developing the disease or disorder. The method includes administering to the subject a therapeutically effective amount of the pharmaceutical composition above.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising an active agent capable of reducing dihydroorotate dehydrogenase (DHODH) enzyme activity in the central nervous system (CNS), and a pyrimidine nucleobase or an intermediate in the de novo synthesis thereof. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein said active agent comprises a nucleic acid molecule that reduces the gene expression level of DHODH enzyme. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein said nucleic acid molecule comprises an shRNA or artificial siRNA molecule comprising a nucleic acid sequence being complementary to a sequence within a nucleic acid sequence encoding said DHODH enzyme, or a nucleic acid molecule encoding said artificial siRNA or shRNA molecule. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein said DHODH enzyme is a human DHODH enzyme. 
     
     
         5 . The pharmaceutical composition of  claim 3 , wherein said shRNA or siRNA molecule comprises a nucleic acid sequence being perfectly complementary to a sequence within said nucleic acid sequence encoding said DHODH enzyme. 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein said active agent is a vector comprising said nucleic acid molecule. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein said vector is a modified virus derived from a virus selected from retrovirus, adenovirus, adeno-associated virus, pox virus, alphavirus, herpes virus, or lentivirus. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein said vector is a modified virus derived from a lentivirus. 
     
     
         9 . The pharmaceutical composition of  claim 6 , wherein said vector comprises a nucleic acid molecule encoding an shRNA molecule comprising a nucleic acid sequence being complementary to a sequence within a nucleic acid sequence encoding said DHODH enzyme. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein said active agent is a small molecule capable of reducing the activity of said DHODH enzyme in said CNS, or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein said active agent is 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflunomide), (2Z)-2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]but-2-enamide (teriflunomide), 6-fluoro-2-[4-(2-fluorophenyl)phenyl]-3-methylquinoline-4-carboxylic acid (brequinar), 3-(3-chlorophenyl)-6,7-dihydro-5H-benzofuran-4-one (DD264), or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein said active agent is teriflunomide, or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The pharmaceutical composition of  claim 1 , wherein said intermediate in the de novo synthesis of pyrimidine nucleobases is uridine, uridine monophosphate (UMP), cytidine, cytidine monophosphate (CMP), deoxythymidine, or deoxythymidine monophosphate (dTMP). 
     
     
         14 . The pharmaceutical composition of  claim 1 , wherein said active agent is teriflunomide, or a pharmaceutically acceptable salt thereof; and said pyrimidine nucleobase or intermediate in the de novo synthesis thereof is uridine, UMP, cytidine, CMP, deoxythymidine, or dTMP. 
     
     
         15 . The pharmaceutical composition of  claim 1 , formulated for intrathecal administration. 
     
     
         16 . A method for treating a disease or disorder associated with cortico-hippocampal hyperactivity in a subject in need thereof, or for preventing or delaying onset of said disease or disorder in a subject diagnosed as suffering from an elevated cortico-hippocampal activity or being at genetic risk for developing said disease or disorder, said method comprising administering to said subject a therapeutically effective amount of a pharmaceutical composition according to  claim 1 . 
     
     
         17 . The method of  claim 16 , for treating a neurodegenerative disease or disorder selected from the group consisting of epilepsy, mild-cognitive impairments (MCI), and Alzheimer's disease. 
     
     
         18 . The method of  claim 17 , wherein said epilepsy is temporal lobe epilepsy (TLE), or Dravet syndrome. 
     
     
         19 . The method of  claim 16 , for preventing sudden unexplained death in epilepsy (SUDEP). 
     
     
         20 . The method of  claim 16 , for preventing or delaying onset of Alzheimer's disease in a subject being at genetic risk for Alzheimer's disease.