Oligoribonucleotides and methods of use thereof for treatment of fibrotic conditions and other diseases

Abstract

The invention relates to a double-stranded compound, preferably an oligoribonucleotide (siRNA), which down-regulates the expression of a human TGaseII gene at the post-transcriptional level. The invention also relates to a pharmaceutical composition comprising the compound, or a vector capable of expressing the oligoribonucleotide compound, and a pharmaceutically acceptable carrier. The present invention also contemplates a method of treating a patient suffering from a fibrotic disease such as pulmonary, kidney and liver fibrosis or ocular, scarring comprising administering to the patient the pharmaceutical composition in a therapeutically effective dose so as to thereby treat the patient. The invention also relates to treatment of fibrotic and other diseases by use of antibodies to TGaseII polypeptide.

1 . A compound having the structure: 
         5′(N) x −Z 3′ (antisense strand) 3′Z′-(N′) y 5′ (sense strand) wherein each N and N′ is a ribonucleotide which may be modified or unmodified in its sugar residue and (N) x  and (N′) y  is an oligomer in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond;    wherein each of x and y is an integer between 19 and 40;    wherein each of Z and Z′ may be present or absent, but if present is dTdT and is covalently attached at the 3′ terminus of the strand in which it is present; and wherein the sequence of (N) x  comprises any one of the sequences set forth in SEQ ID NOS: 21-38, 192-344 and 381-416.    
     
     
         2 . The compound of  claim 1 , wherein the covalent bond is a phosphodiester bond.  
     
     
         3 . The compound of  claim 2 , wherein x=y.  
     
     
         4 . The compound of  claim 3 , wherein x=y=19.  
     
     
         5 . The compound of  claim 1  wherein Z and Z′ are both absent.  
     
     
         6 . The compound of  claim 1  wherein one of Z or Z′ is present.  
     
     
         7 . The compound of  claim 1  wherein all of the ribonucleotides are unmodified in their sugar residues.  
     
     
         8 . The compound of  claim 1  wherein at least one ribonucleotide is modified in its sugar residue.  
     
     
         9 . The compound of  claim 8 , wherein the modification of the sugar residue comprises a modification at the 2′ position.  
     
     
         10 . The compound of  claim 9 , wherein the modification at the 2′ position results in the presence of a moiety selected from the group comprising amino, fluoro, methoxy, alkoxy and alkyl groups.  
     
     
         11 . The compound of  claim 10 , wherein the moiety at the 2′ position is methoxy (2′-0-methyl).  
     
     
         12 . The compound of  claim 1  wherein alternating ribonucleotides are modified in both the antisense and the sense strands.  
     
     
         13 . The compound of  claim 1  wherein the ribonucleotides at the 5′ and 3′ termini of the antisense strand are modified in their sugar residues, and the ribonucleotides at the 5′ and 3′ termini of the sense strand are unmodified in their sugar residues.  
     
     
         14 . The compound of  claim 1  wherein the antisense strand is phophorylated at the 5′ terminus, and may or may not be phophorylated at the 3′ terminus; and 
 wherein the sense strand may or may not be phophorylated at the 5′ terminus and at the 3′ terminus.    
     
     
         15 . A vector capable of expressing the compound of  claim 1 .  
     
     
         16 . A composition comprising the compound of  claim 1  in an amount effective to inhibit human TGaseII and a carrier.  
     
     
         17 . A method of treating a patient suffering from a disorder comprising administering to the patient an inhibitor of human TGaseII in a therapeutically effective dose so as to thereby treat the patient.  
     
     
         18 . The method of  claim 17 , where the inhibitor is an siRNA.  
     
     
         19 . The method of  claim 17 , where the inhibitor is an antibody.  
     
     
         20 . (canceled)  
     
     
         21 . The method of  claim 17 , wherein the disorder is a fibrosis-related pathology.  
     
     
         22 . The method of  claim 21 , wherein the fibrosis-related pathology is kidney fibrosis, liver fibrosis, pulmonary fibrosis or ocular scarring.  
     
     
         23 . The method of  claim 17 , wherein the disorder is any one of an ocular disease especially cataract, a cardiovascular disease especially cardiac hypertrophy, atherosclerosis/restenosis, a neurological disease, including polyglutamine disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, spinocerebellar ataxias (SCAs) 1, 2, 3, 6, 7 and 17, Alzheimer's disease or Parkinson's disease.  
     
     
         24 . A composition comprising the vector of  claim 15  in an amount effective to inhibit human TGaseII and a carrier.  
     
     
         25 . A method of treating a patient suffering from a disorder comprising administering to the patient the compounds of  claim 1  in a therapeutically effective dose so as to thereby treat the patient.  
     
     
         26 . A method of treating a patient suffering from a disorder comprising administering to the patient the vector of  claim 15  in a therapeutically effective dose so as to thereby treat the patient.