RNAi-MEDIATED INHIBITION OF HIF1A FOR TREATMENT OF OCULAR ANGIOGENESIS

Abstract

RNA interference is provided for inhibition of HIF1A mRNA expression for treating patients with ocular angiogenesis, particularly for treating retinal edema, diabetic retinopathy, sequela associated with retinal ischemia, posterior segment neovascularization (PSNV), and neovascular glaucoma, and for treating patients at risk of developing such conditions.

What is claimed is: 
     
         1 . A composition for attenuating expression of a hypoxia-inducible factor-la (HIF1A) gene, the composition comprising an interfering RNA having a length of 19 to 49 nucleotides, wherein the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence identity with UAUGUGGAAGUGGCAACUG (SEQ ID NO: 53). 
     
     
         2 . The composition of  claim 1 , wherein the interfering RNA is single-stranded, a shRNA, a double-stranded siRNA, or a miRNA. 
     
     
         3 . The composition of  claim 2 , wherein at least one of the nucleotides of the interfering RNA is modified on its base portion, sugar portion, or phosphate portion. 
     
     
         4 . The composition of  claim 3 , wherein at least one of the nucleotides of the interfering RNA has a 2′-0-methyl modification. 
     
     
         5 . The composition of  claim 3 , wherein the interfering RNA comprises a region of at least 15, 16, 17, 18, or 19 contiguous nucleotides of UAUGUGGAAGUGGCAACUG (SEQ ID NO: 53). 
     
     
         6 . The composition of  claim 3 , wherein the interfering RNA is a double-stranded siRNA comprising a first strand and a second strand, and wherein each strand of the double-stranded siRNA has a length of 19 to 49 nucleotides. 
     
     
         7 . The composition of  claim 6 , wherein the first strand of the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence identity with UAUGUGGAAGUGGCAACUG (SEQ ID NO: 53), and the second strand of the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence identity with 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 52) 
                 
                     
                   CAGUUGCCACUUCCACAUA. 
                 
             
                
                
               
            
           
         
       
     
     
         8 . The composition of  claim 7 , wherein at least one of the nucleotides of the first stand and at least one of the nucleotides of the second strand of the interfering RNA is modified on its base portion, sugar portion, or phosphate portion. 
     
     
         9 . The composition of  claim 1 , wherein the composition further comprises 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% complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′ end of an mRNA corresponding to any one of SEQ ID NO: 3, and SEQ ID NO:9 — SEQ ID NO:51. 
     
     
         10 . A method of attenuating expression of HIF1A mRNA in a subject, the method comprising administering to the subject an effective amount of the composition of  claim 1 , wherein the expression of HIF1A mRNA is thereby attenuated. 
     
     
         11 . The method of  claim 10 , wherein the interfering RNA is single-stranded, a shRNA, a double-stranded siRNA, or a miRNA. 
     
     
         12 . The method of  claim 11 , wherein at least one of the nucleotides of the interfering RNA is modified on its base portion, sugar portion, or phosphate portion. 
     
     
         13 . The method of  claim 12 , wherein at least one of the nucleotides of the interfering RNA has a 2′-0-methyl modification. 
     
     
         14 . The method of  claim 12 , wherein the interfering RNA comprises a region of at least 15, 16, 17, 18, or 19 contiguous nucleotides of UAUGUGGAAGUGGCAACUG (SEQ ID NO: 53). 
     
     
         15 . The method of  claim 12 , wherein the interfering RNA is a double-stranded siRNA comprising a first strand and a second strand, and wherein each strand of the double-stranded siRNA has a length of 19 to 49 nucleotides. 
     
     
         16 . The method of  claim 15 , wherein the first strand of the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence identity with UAUGUGGAAGUGGCAACUG (SEQ ID NO: 53), and the second strand of the interfering RNA comprises a region of at least 13 contiguous nucleotides having at least 90% sequence identity with 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 52) 
                 
                     
                   CAGUUGCCACUUCCACAUA. 
                 
             
                
                
               
            
           
         
       
     
     
         17 . The method of  claim 10 , the method further comprising administering to the subject an effective amount of 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% complementarity to, or at least 90% sequence identity with, the penultimate 13 nucleotides of the 3′ end of an mRNA corresponding to any one of SEQ ID NO: 3, and SEQ ID NO:9 — SEQ ID NO:51. 
     
     
         18 . The method of  claim 10 , wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route. 
     
     
         19 . The method of  claim 16 , wherein the composition is administered via a topical, intravitreal, transcleral, periocular, conjunctival, subtenon, intracameral, subretinal, subconjunctival, retrobulbar, or intracanalicular route.