RNAi-Mediated Inhibition of Frizzled Related Protein-1 for Treatment of Glaucoma

Abstract

RNA interference is provided for inhibition of Frizzled Related Protein-1 mRNA expression, in particular, for treating patients having glaucoma or at risk of developing glaucoma.

What is claimed is: 
     
         1 . An interfering RNA comprising: a sense nucleotide strand, an antisense nucleotide strand, and comprising a nucleotide sequence corresponding to any one of SEQ ID NO:2, SEQ ID NO:8-SEQ ID NO:190, and SEQ ID NO:192 wherein one or more thymines, if present, is replaced with a uracil, or a complement thereof. 
     
     
         2 . The interfering RNA of  claim 1  wherein the 5′ end of the sense strand, the antisense strand, or both the sense strand and the antisense strand are phosphorylated. 
     
     
         3 . The interfering RNA of  claim 1  wherein the sense strand, the antisense strand, or both the sense strand and the antisense strand have a 3′ overhang of from 1 to 6 nucleotides. 
     
     
         4 . The interfering RNA of  claim 1  wherein one or more nucleotides is modified. 
     
     
         5 . The interfering RNA of  claim 1  wherein the one or more modified nucleotides independently comprise a nucleotide wherein a 2′-OH group is replaced by 2′-amino group, 2′-O-methyl group, 2′-methoxyethyl group, or a 2′-O,4′-C methylene bridge. 
     
     
         6 . The interfering RNA of  claim 1  wherein the one or more modified nucleotides are independently modified on their base portion, on their sugar portion, or on their phosphate portion. 
     
     
         7 . The interfering RNA of  claim 1  wherein one or more phosphate groups is modified my substituting a phosphorothioate. 
     
     
         8 . The interfering RNA of  claim 1  wherein one of more nucleotides is modified by covalent addition of a non-nucleotide molecule or functional group. 
     
     
         9 . The interfering RNA of  claim 8  non-nucleotide molecule or functional group is bound to the 5′ end or the 3′ end of the sense strand and/or the antisense strand. 
     
     
         10 . A composition comprising an interfering RNA having a length of 19 to 49 nucleotides, and comprising an nucleotide sequence corresponding to any one of SEQ ID NO:2, SEQ ID NO:8-SEQ ID NO:190, and SEQ ID NO:192 wherein one or more thymines, if present, are replaced with uracils, or a complement thereof; and a pharmaceutically acceptable carrier. 
     
     
         11 . The composition of  claim 10  wherein the 5′ end of the sense strand, the antisense strand, or both the sense strand and the antisense strand are phosphorylated. 
     
     
         12 . The composition of  claim 10  wherein the sense strand, the antisense strand, or both the sense strand and the antisense strand have a 3′ overhang of from 1 to 6 nucleotides. 
     
     
         13 . The composition of  claim 10  wherein one or more nucleotides is modified. 
     
     
         14 . The composition of  claim 10  wherein the one or more modified nucleotides independently comprise a nucleotide wherein a 2′-OH group is replaced by 2′-amino group, 2′-O-methyl group, 2′-methoxyethyl group, or a 2′-O,4′-C methylene bridge. 
     
     
         15 . The composition of  claim 10  wherein the one or more modified nucleotides are independently modified on their base portion, on their sugar portion, or on their phosphate portion. 
     
     
         16 . The composition of  claim 10  wherein one or more phosphate groups is modified my substituting a phosphorothioate. 
     
     
         17 . The composition of  claim 10  wherein one of more nucleotides is modified by covalent addition of a non-nucleotide molecule or functional group. 
     
     
         18 . The composition of  claim 17  non-nucleotide molecule or functional group is bound to the 5′ end or the 3′ end of the sense strand and/or the antisense strand. 
     
     
         19 . The composition of  claim 10  further comprising a second interfering RNA having a length of 19 to 49 nucleotides and comprising a region of at least 13 contiguous nucleotides having at least 90% sequence complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′ end of any one of SEQ ID NO:2, SEQ ID NO:8—SEQ ID NO:190, and SEQ ID NO:192. 
     
     
         20 . A method of attenuating expression of Frizzled Related Protein-1 mRNA in a subject, comprising:
 administering to the subject a composition comprising an effective amount of interfering RNA and a pharmaceutically acceptable carrier, the interfering RNA comprising:   a sense nucleotide strand, an antisense nucleotide strand, and a region of at least near-perfect contiguous complementarity of at least 19 nucleotides;   wherein the antisense strand is 19 to 49 nucleotides and hybridizes to a nucleic acid sequence of any one of SEQ ID NO: 2, SEQ ID NO: 8—SEQ ID NO: 17, SEQ ID NO: 19—SEQ ID NO: 190, and SEQ ID NO: 192, wherein the thymines are replaced with uracils,   wherein the expression of Frizzled Related Protein-1 mRNA is attenuated thereby.