Means and methods for the specific modulation of target genes in the cns and the eye and methods for their identification

Abstract

Provided are methods for the treatment of disorders of the central nervous system (CNS) and the eye. In particular, use of compositions comprising a compound capable of modulating a target gene or gene product is described for the preparation of a pharmaceutical composition for the treatment of disorders of the CNS and/or the eye, wherein the composition is designed to be administered outside the blood-CNS and the blood-retina barriers. Furthermore, methods are provided for identifying and obtaining nucleic acid molecules encoding polypeptides involved in CNS disorders or of the eye, methods for diagnosing said disorders as well as transgenic animal deficient in the expression of target genes identified in accordance with the described method. In addition, methods of identifying and isolating drugs that are particularly useful for the treatment of disorders related to the CNS and/or the eye are disclosed.

1 - 90 . (canceled) 
     
     
         91 . A method for the treatment of a disorder of the central nervous system (CNS) and/or the eye comprising administering to a subject a composition comprising a compound capable of modulating a target gene or gene product in a therapeutically effective amount, wherein said composition is administered outside the blood-brain and/or the blood-retina barriers. 
     
     
         92 . The method of  claim 91 , wherein the disorder is an eye disorder. 
     
     
         93 . The method  claim 91 , wherein said disorder is a disorder of angiogenesis and/or neovascularization. 
     
     
         94 . The method of  claim 91 , wherein the disorder is a disorder of the retinal pigment epithelium (RPE), neurosensory retina and/or choriodea. 
     
     
         95 . The method of  claim 91 , wherein said disorder is wet age-related macular degeneration (AMD) or diabetic retinopathy. 
     
     
         96 . The method of  claim 91 , wherein the composition is effective to be applied outside the retinal region of the blood-retina barrier and cross the blood-retina barrier. 
     
     
         97 . The method of  claim 91 , wherein the compound is an inhibitor/antagonist of said target gene or gene product. 
     
     
         98 . The method of  claim 91 , wherein said antagonist/inhibitor inhibits the expression of a gene or the activity of a gene product involved in angiogenesis and/or neovascularization. 
     
     
         99 . The method of  claim 91 , wherein said antagonist/inhibitor is or is derived from an nucleic acid molecule, polypeptide, antibody, or a ligand binding molecule of said gene or gene product. 
     
     
         100 . The method of  claim 91 , wherein said antagonist/inhibitor is a ribozyme, antisense or sense nucleic acid molecule to said gene or gene product. 
     
     
         101 . The method of  claim 91 , wherein said antagonist/inhibitor substantially consists of ribonucleotides. 
     
     
         102 . The method of  claim 91 , wherein said antagonist/inhibitor comprises substantially a portion of double-stranded oligoribonucleotides (dsRNA). 
     
     
         103 . The method of  claim 91 , wherein said dsRNA is between 21 and 23 nucleotides in length. 
     
     
         104 . The method of  claim 91 , wherein the dsRNA molecule contains a terminal 3′-hydroxyl group. 
     
     
         105 . The method of  claim 100 , wherein the nucleic acid molecule represents an analogue of naturally occurring RNA. 
     
     
         106 . The method of  claim 100 , wherein the nucleotide sequence of the nucleic acid molecule differs from the nucleotide sequence of said gene or gene product by addition, deletion, substitution or modification of one or more nucleotides. 
     
     
         107 . The method of  claim 91 , wherein said compound is a nucleic acid molecule or encoded by a nucleic acid molecule and is designed to be expressed in cells of the CNS or eye. 
     
     
         108 . The method of  claim 91 , wherein the composition is designed for systemic administration or for administration by iontophoresis composition is designed for retrobulbar application or as eye drops 
     
     
         109 . A pharmaceutical composition effective to cross the blood-retina barrier, wherein the composition comprises a compound capable of modulating a target gene or gene product inside the blood-brain or blood-retina barrier in a therapeutically effective amount. 
     
     
         110 . The pharmaceutical composition of  claim 109 , wherein the compound is a double-stranded oligoribonucleotide molecule (dsRNA).