Methods and compositions for treating urea cycle disorders

Abstract

Provided are methods and compositions for the treating a patient with a urea cycle disorder. Methods and compositions are also provided for modulating genes encoding enzymes that participate in the urea cycle by altering gene signaling networks.

1 . A method for increasing OTC gene expression in a cell harboring an OTC mutation associated with a partial reduction of OTC function, comprising: contacting the cell with an effective amount of a compound that increases CPS1 expression, wherein the compound inhibits a target selected from the group consisting of JAK1, JAK2, JAK3, and IRF9. 
     
     
         2 . The method of  claim 1 , wherein the cell is a hepatocyte. 
     
     
         3 . The method of  claim 1 , wherein the target is JAK1, JAK2 or JAK3. 
     
     
         4 . The method of  claim 3 , wherein the target is JAK1. 
     
     
         5 . The method of  claim 3 , wherein the compound is selected from the group consisting of tofacitinib, momelotinib, baricitinib, upadacitinib, oclacitinib maleate, GLPG0634, GLPG0634 analog, LYS2784544, ruxolitinib, itacitinib, AZD1480, CP690550 citrate, cerdulatinib, decernotinib, peficitinib, and PF-06263276. 
     
     
         6 . The method of  claim 5 , wherein the compound is tofacitinib. 
     
     
         7 . The method of  claim 1 , wherein the compound is an siRNA. 
     
     
         8 . A method for increasing OTC expression in a human subject harboring an OTC mutation associated with a partial reduction of OTC function, comprising: administering to the subject an effective amount of a compound that increases CPS1 expression, wherein the compound inhibits a target selected from the group consisting of JAK1, JAK2, JAK3, and IRF9. 
     
     
         9 . The method of  claim 8 , wherein the subject is human. 
     
     
         10 . The method of  claim 8 , wherein the target is JAK1, JAK2 or JAK3. 
     
     
         11 . The method of  claim 10 , wherein the target is JAK1. 
     
     
         12 . The method of  claim 11 , wherein the compound is selected from the group consisting of tofacitinib, momelotinib, baricitinib, upadacitinib, oclacitinib maleate, GLPG0634, GLPG0634 analog, LYS2784544, ruxolitinib, itacitinib, AZD1480, CP690550 citrate, cerdulatinib, decernotinib, peficitinib, and PF-06263276. 
     
     
         13 . The method of  claim 12 , wherein the compound is tofacitinib. 
     
     
         14 . The method of  claim 8 , wherein the compound is an siRNA.