Methods for Altering MRNA Splicing and Treating Familial Dysautonomia and Other Mechanistically Related Disorders

Abstract

This invention relates to methods for altering the splicing of mRNA in cells. In particular, this invention also relates to methods for increasing the ratio of wild type to misspliced forms of mRNA and corresponding encoded proteins in cells possessing a mutant gene encoding either the i) misspliced mRNA corresponding to the mutant protein or ii) a component in the splicing machinery responsible for processing the misspliced mRNA. In addition, this invention relates to treating individuals having a disorder associated with a misspliced mRNA, such as Familial Dysautonomia or Neurofibromatosis 1, by administering to such an individual a cytokinin such as kinetin.

1 - 45 . (canceled) 
     
     
         46 . A method for treating neuronal degeneration in a subject in need thereof comprising administering to said subject a composition that comprises an effective concentration, of one or more 6-(substituted amino)purine cytokinins selected from the group consisting of the compounds of kinetin, benzyl adenine, isopentenyl adenine, (6-(3-hydroxymethyl-3-methylallyl)-aminopyrine), 6-(3,3-dimethylallyl)aminopyrine, 6-(benzyl)aminopyrine, 6-(phenyl)aminopyrine, 6-(n-alkyl)aminopyrine, in which the n-alkyl group has 4, 5, or 6 carbons, 6-(cyclohexyl)methylaminopurine, and those compounds of Formula I, 
       
         
           
           
               
               
           
         
       
       in which R 1  is furfuryl, phenyl, benzyl, n-alkyl of 4, 5, or 6 carbons, branched alkyl of 4, 5, or 6 carbons, (cyclohexyl)methyl, 3,3-dimethylallyl, and 3-hydroxymethyl -3-methylallyl. 
     
     
         47 . (canceled) 
     
     
         48 . A method for treating neuronal degeneration or familial dysautonomia in a subject in need thereof, comprising administering to said subject an effective amount of a composition that comprises one or more cytokinins, one or more cytokinins and one or more tocotrienols, or one or more cytokinins and (−)-epigallocatechin gallate. 
     
     
         49 . The method according to  claim 48 , wherein at least one of the one or more tocotrienols is tocotrienols selected from the group consisting of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. 
     
     
         50 . The method according to  claim 48 , wherein at least one of the one or more tocotrienols is δ-tocotrienol. 
     
     
         51 - 54 . (canceled) 
     
     
         55 . The method according to  claims 46  or  48  wherein the subject is a mammal. 
     
     
         56 . The method according to  claims 46  or  48  wherein the subject is a human. 
     
     
         57 . The method according to  claim 48 , wherein at least one of the one or more cytokinins selected from the group consisting of benzyladenine and kinetin. 
     
     
         58 . The method according to  claim 48 , wherein at least one of the one or more cytokinins is kinetin. 
     
     
         59 . A method of treating familial dysautonomia in a subject in need thereof, comprising administering to said subject a composition that comprises an effective concentration of one or more 6-(substituted amino)purine cytokinins selected from the group consisting of the compounds of kinetin, benzyladenine, isopentenyl adenine, (6-(3-hydroxymethyl-3-methylallyl)-aminopyrine), 6-(3,3-dimethylally)aminopyrine, 6-(benzyl)aminopyrine, 6-(phenyl)aminopyrine, 6-(n-alkyl)aminopyrine, in which the n-alkyl group has 4, 5, or 6 carbons, 6-(cyclohexyl)methylaminopurine, and those compounds of Formula I, 
       
         
           
           
               
               
           
         
       
       in which R 1  is furfuryl, phenyl, benzyl, n-alkyl of 4, 5, or 6 carbons, branched alkyl of 4, 5, or 6 carbons, (cyclohexyl)methyl, 3,3-dimethylallyl, and 3-hydroxymethyl-3-methylallyl. 
     
     
         60 . (canceled) 
     
     
         61 . The method according to  claim 59 , wherein at least one of the one or more tocotrienols selected from the group consisting of α-tocotrienol, β-tocotrienol, γ-tocotrienol, and δ-tocotrienol. 
     
     
         62 . The method according to  claim 59 , wherein at least one of the one or more tocotrienols is δ-tocotrienol. 
     
     
         63 - 135 . (canceled) 
     
     
         136 . The method according to  claim 59 , wherein the subject is a mammal. 
     
     
         137 . The method according to  claim 59 , wherein the subject is a human.