Methods and compositions for detecting and treating retinal diseases

Abstract

The invention discloses multiple genes related to age-related macular degeneration (AMD) and/or phagocytosis by RPE cells of the eye, and methods and compositions for detecting and treating AMD and other retinal degenerative conditions based on these phagocytosis-related and/or AMD-related genes. Also provided are nonhuman transgenic animal models useful for testing therapeutic compounds and treatment protocols for AMD, and gene arrays including polymorphic variants of phagocytosis-related and/or AMD-related genes, useful for genetic screening of nucleic acid samples from subjects to obtain profiles of polymorphic variant sequences in a plurality of genes associated with AMD. Several preferred embodiments of the therapeutic compositions and animal models are based on target genes MT1-MMP and casein kinase 1 epsilon (CK1ε), phagocytosis-related genes found to be over-expressed in human donor eye samples from patients having both wet and dry forms of AMD.

1 . A method for treating a subject having a retinal or choroidal degenerative disease or condition comprising administering to the eye of said subject an antibody that specifically binds to a casein kinase 1 epsilon protein or peptide. 
     
     
         2 . The method of  claim 1 , wherein said protein is a human casein kinase 1 epsilon encoded by the nucleic acid sequence set forth as SEQ ID NO:9, or a polymorphic variant thereof. 
     
     
         3 . The method of  claim 1 , wherein said retinal or choroidal degenerative disease or condition is the wet or dry form of age-related macular degeneration (AMD). 
     
     
         4 . The method of  claim 1 , wherein said antibody contacts a retinal cell type selected from a photoreceptor, an RPE cell, or a Muller cell, or a cell type of the choroid selected from an endothelial cell, a smooth muscle cell, a leukocyte, a macrophage, a melanocyte or a fibroblast. 
     
     
         5 . The method of  claim 1 , wherein the antibody is administered by intraocular injection. 
     
     
         6 . The method of  claim 1 , wherein the antibody is selected from the group consisting of a polyclonal antibody, a monoclonal antibody, a single chain antibody, an Fab fragment and an (Fab′) 2  fragment. 
     
     
         7 . The method of  claim 1 , wherein the antibody is produced using a Fab library. 
     
     
         8 . A method for treating a subject having a retinal or choroidal degenerative disease or condition comprising administering to the eye of said subject an inhibitory oligonucleotide that specifically downregulates the expression of casein kinase 1 epsilon, selected from the group consisting of a ribozyme, an antisense RNA, an interfering RNA (RNAi) molecule, a small inhibitory RNA (siRNA) molecule, and a triple helix forming molecule. 
     
     
         9 . The method of  claim 8 , wherein the inhibitory oligonucleotide is a siRNA molecule. 
     
     
         10 . The method of  claim 9 , wherein the siRNA molecule is a double-stranded RNA molecule consisting of the nucleotide sequences set forth as SEQ ID NOS:138 and 139. 
     
     
         11 . A nonhuman transgenic animal comprising an isolated nucleic acid construct comprising a transgene driven by a promoter, wherein said construct causes over-expression, in at least one cell type of said animal, of a gene that is over-expressed in the eyes of human subjects with AMD, selected from the group consisting of membrane type matrix metalloproteinase 1 (MT1-MMP), casein kinase 1 epsilon (CK1ε), prostaglandin D2 synthase, and gene AMDP-3. 
     
     
         12 . The nonhuman transgenic animal of  claim 11 , wherein said over-expression is conditionally controlled. 
     
     
         13 . The nonhuman transgenic animal of  claim 11 , wherein said cell type is a retinal cell type selected from the group of consisting of a photoreceptor, an RPE cell, and a Muller cell, or a choroidal cell type selected from the group consisting of an endothelial cell, a smooth muscle cell, a leukocyte, a macrophage, a melanocyte, and a fibroblast. 
     
     
         14 . The nonhuman transgenic animal of  claim 12 , wherein the transgene comprises a sequence that encodes MT1-MMP. 
     
     
         15 . The nonhuman transgenic animal of  claim 12 , wherein the transgene comprises a sequence that encodes CK1 epsilon.