Compositions and methods for the treatment of retinal degeneration

Abstract

The present invention relates to a pharmaceutical composition comprising an inhibitor of eIF2α, a compound increasing the expression and/or activity of protein BiP and/or an inhibitor of Caspase-12, preferably an inhibitor of eIF2α and a compound increasing the expression and/or activity of protein BiP. The present invention also relates to pharmaceutical compositions and methods for treating retinal degeneration related to ciliary dysfunction.

We claim: 
     
         1 . A pharmaceutical composition comprising an inhibitor of eIF2α, a compound increasing the expression and/or activity of protein BiP, and a pharmaceutically acceptable carrier and/or excipient, wherein said inhibitor of eIF2α is selected from the group consisting of inhibitors of GADD 34, and inhibitors of the PP1/GADD34 complex. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the compound increasing the expression and/or activity of protein BiP is selected from the group consisting of valproic acid or a derivative thereof, trichostatin A, lithium, 1-(3,4-dihydroxy-phenyl)-2-thiocyanate-ethanone, and exendin-4. 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein the compound increasing the expression and/or activity of protein BiP is valproic acid or 2-ene-valproic acid. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the compound increasing the expression and/or activity of protein BiP is valproic acid. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the inhibitor of eIF2-α is an inhibitor of GADD34. 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the inhibitor of GADD34 is guanabenz or a nucleic acid molecule specifically interfering with GADD34 expression. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the inhibitor of GADD34 is guanabenz. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the inhibitor of eIF2-α is an inhibitor of the PP1/GADD34 complex. 
     
     
         9 . The pharmaceutical composition of  claim 8  wherein the inhibitor of the PP1/GADD34 complex is salubrinal or a compound inhibiting the formation of the PP1/GADD34 complex. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the compound increasing the expression and/or activity of protein BiP is valproic acid and the inhibitor of elF2α is guanabenz. 
     
     
         11 . The pharmaceutical composition of  claim 1 , further comprising an inhibitor of caspase-12. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the inhibitor of caspase-12 is selected from the group consisting of a peptide targeting the catalytic site of caspase-12, a peptide preventing the cleavage of procaspase-12 and a nucleic acid molecule specifically interfering with caspase-12 expression. 
     
     
         13 . The pharmaceutical composition of  claim 11 , wherein the compound increasing the expression and/or activity of protein BiP is valproic acid and the inhibitor of elF2α is guanabenz. 
     
     
         14 . The pharmaceutical composition of  claim 1 , further comprising at least one additional therapeutic agent. 
     
     
         15 . A method of treating retinal degeneration related to ciliary dysfunction comprising the administration of a pharmaceutical composition of  claim 1 , to a subject having retinal degeneration related to ciliary dysfunction. 
     
     
         16 . The method of  claim 15 , wherein the retinal degeneration is induced by a ciliopathy selected from the group consisting of Bardet Biedl syndrome, Senior-Loken syndrome, Joubert syndrome, Salidono-Mainzer syndrome, Sensenbrenner syndrome, Jeune syndrome, Meckel-Gruber syndrome, Alström syndrome, MORM syndrome, Leber's congenital amaurosis caused by mutation in a ciliary gene and X-linked retinitis pigmentosa caused by mutation in the RPGR gene. 
     
     
         17 . The method of  claim 16 , further comprising the administration of an inhibitor of caspase-12. 
     
     
         18 . The method of  claim 17 , wherein said method comprises administering said pharmaceutical composition topically, orally, intradermally, parenterally or intraocularly. 
     
     
         19 . The method of  claim 18 , wherein said method comprises topical ocular or peri-ocular administration of said pharmaceutical composition.