Treating Ocular Diseases Using Peroxisome Proliferator-Activated Receptor Delta Antagonists

Abstract

The present invention provides novel agents, expression constructs, compositions and methods useful for treating an ocular disease associated with unwanted PPARδ activity through the modulation of PPARδ expression The PPARδ interference RNA (iRNA) agents, expression constructs encoding such agents, and compositions comprising such agents or constructs are directed against RNA molecules encoding PPARδ The methods comprise treating an ocular disease associated with unwanted PPARδ activity in a patient in need thereof by administering an effective amount of a pharmaceutical composition comprising a PPARδ iRNA agent or expression construct encoding such agent to the patient to reduce a symptom associated with unwanted PPARδ activity in the patient.

1 . A PPARδ iRNA agent comprising a duplex region directed towards a PPARδ target sequence, the duplex region comprising
 a) a sense sequence comprising a nucleic acid sequence identical to or substantially identical to the PPARδ target sequence, wherein the sense strand that is substantially identical to the PPARδ target sequence differs in identity from the PPARδ target sequence by no more than five nucleotides; and   b) an anti-sense sequence comprising a nucleic acid sequence complementary to or substantially complementary to the PPARδ target sequence, wherein the sense strand that is substantially complementary to the PPARδ target sequence differs in complementarity from the PPARδ target sequence by no more than five nucleotides; and   wherein the PPARδ target sequence is a nucleic acid sequence selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55. SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72.   
     
     
         2 . The PPARδ iRNA agent of  claim 1 , wherein the PPARδ iRNA agent is a single-stranded PPARδ iRNA agent. 
     
     
         3 . The PPARδ iRNA agent of  claim 1 , wherein the PPARδ iRNA agent is a double-stranded PPARδ iRNA agent. 
     
     
         4 . The PPARδ iRNA agent of  claim 1 , wherein the anti-sense sequence comprises a 3′-end overhang. 
     
     
         5 . The PPARδ iRNA agent of  claim 4 , wherein the 3′-end overhang is 1, 2, or 3 nucleotides in length. 
     
     
         6 . The PPARδ iRNA agent of  claim 1 , wherein the PPARδ iRNA agent comprises a modification in the sense sequence, the anti-sense sequence, or both sense sequence and the anti-sense sequence. 
     
     
         7 . The PPARδ iRNA agent of  claim 6 , wherein the location of the modification is on a 3′-end nucleotide, a 5′-end nucleotide, or both a 3′-end nucleotide and a 5′-end nucleotide. 
     
     
         8 . An expression construct comprising an expression vector and a PPARδ iRNA agent of  claim 1 . 
     
     
         9 . The expression construct of  claim 8 , wherein the expression vector is a viral expression construct. 
     
     
         10 . The expression construct of  claim 9 , wherein the viral expression vector is derived from a virus selected from the group consisting of an adeno-associated virus, a retrovirus, an adenovirus, and an alphavirus. 
     
     
         11 . A pharmaceutical composition comprising
 a) PPARδ iRNA agent of  claim 8 ; and   b) a pharmaceutically acceptable carrier.   
     
     
         12 . A composition comprising a PPARδ iRNA agent of  claim 1 . 
     
     
         13 . A pharmaceutical composition comprising
 a) PPARδ iRNA agent of  claim 12 ; and   b) a pharmaceutically acceptable carrier.   
     
     
         14 . A method of treating an ocular disease associated with an unwanted PPARδ activity in a patient in need thereof, the method comprising the step of administering an effective amount of a pharmaceutical composition of  claim 13 , wherein administration of the pharmaceutical composition reduces a symptom associated with unwanted PPARδ activity in the patient. 
     
     
         15 . The method of  claim 14 , wherein ocular disease associated with an unwanted PPARδ activity is selected from the group consisting of wet Age-Related Macular Degeneration, dry Age-Related Macular Degeneration, Best's vitelliform macular degeneration, glaucoma, retinitis pigmentosa, diabetic retinopathy, macular edema, a degenerative disease of photoreceptors and a degenerative disease of the retinal pigment epithelium. 
     
     
         16 . The method of  claim 14 , wherein ocular disease associated with an unwanted PPARδ activity is an ocular disease involving abnormal intraocular cellular proliferation. 
     
     
         17 . The method of  claim 16 , wherein ocular disease involving abnormal intraocular cellular proliferation is selected from the group consisting of proliferative diabetic disease, retinopathy of prematurity, proliferative vitreoretinopathy, retinal-choroidal anastomosis, retinal angiomatous proliferation, retinal vein occlusion, neovascular glaucoma, diabetic retinopathy, retinoblastoma and uveal melanoma. 
     
     
         18 . The method of  claim 14 , wherein administration of the pharmaceutical composition to the patient is by a cellular uptake approach. 
     
     
         19 . The method of  claim 18 , wherein the cellular uptake approach is selected from the group consisting of a topical administration, an injection and a placement device. 
     
     
         20 . The method of  claim 19 , wherein the placement device is an intraocular implant. 
     
     
         21 . The method of  claim 14 , wherein administration of the pharmaceutical composition to the patient is by a gene therapy approach. 
     
     
         22 . A method of treating an ocular disease associated with an unwanted PPARδ activity in a patient in need thereof, the method comprising the step of administering an effective amount of a pharmaceutical composition of  claim 11 , wherein administration of the pharmaceutical composition reduces a symptom associated with unwanted PPARδ activity in the patient.