Use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization

Abstract

The use of compounds that interfere with the hedgehog signaling pathway for the manufacture of a medicament for preventing, inhibiting, and/or reversing ocular diseases related with ocular neovascularization. Particularly, the above-mentioned diseases are (wet) age-related macular degeneration, (proliferative) diabetic retinopathy, neovascular glaucoma, retinal vein occlusion, or retinopathy of prematurity (ROP).

1 . A method of inhibiting, and/or reversing disease related with ocular neovascularization in a mammalian subject comprising:
 administering to the subject a therapeutically effective amount of a substance that interferes with the Hedgehog signaling pathway,   wherein said substance is one of:   (i) a soluble Hip1 protein encoded in a transgene cassette of a gene transfer vector, wherein the administration of said gene transfer vector to a mammalian subject results in the expression and secretion of soluble Hip 1,   and   (ii) a small interfering (ribo)nucleic acid.   
     
     
         2 . The method of  claim 1 , wherein,
 the substance is said soluble Hip1 protein encoded in a transgene cassette of a gene transfer vector, and   said soluble Hip1 protein is SEQ ID NO 6 or a homologous protein.   
     
     
         3 . The method of  claim 1 , wherein,
 the substance is said soluble Hip1 protein encoded in a transgene cassette of a gene transfer vector, and   said soluble Hip1 protein is obtained from RIP1 by deletion of the transmembrane segment located at the C-terminus, and optionally containing a signal peptide.   
     
     
         4 . The method of  claim 1 , wherein,
 the substance is said soluble Hip1 protein encoded in a transgene cassette of a gene transfer vector, and   said soluble Hip1 protein is SEQ ID NO 4.   
     
     
         5 . The method of  claim 1 , wherein,
 the substance is said soluble Hip1 protein encoded in a transgene cassette of a gene transfer vector, and   said gene transfer vector is a recombinant adeno-associated viral vector.   
     
     
         6 . The method of  claim 1 , wherein,
 the substance is an isolated small interfering RNA which comprises a sense RNA strand and an antisense RNA strand,   the sense and antisense RNA strands form an RNA duplex,   the sense RNA strand comprises nucleotide sequence SEQ ID NO: 16, and   the antisense RNA strand comprises the nucleotide sequence SEQ ID NO: 15.   
     
     
         7 . The method of  claim 1 , wherein,
 the substance is an isolated small interfering RNA which comprises a sense RNA strand and an antisense RNA strand,   the sense and antisense RNA strands form an RNA duplex,   the sense RNA strand comprises a nucleotide sequence SEQ ID NO: 17, and   the antisense RNA strand comprises the nucleotide sequence SEQ ID NO:18.   
     
     
         8 . The method of  claim 1 , wherein,
 the substance is an isolated small interfering RNA which comprises a sense RNA strand and an antisense RNA strand,   the sense and antisense RNA strands form an RNA duplex,   the sense RNA strand comprises the nucleotide sequence SEQ ID NO: 19, and   the antisense RNA strand comprises the nucleotide sequence SEQ ID NO: 20.   
     
     
         9 . The method of  claim 1 , wherein,
 the substance is a DNA sequence corresponding to said small interfering (ribo)nucleic acid, and   said DNA sequence is comprised in a transgene cassette of a recombinant adeno-associated viral vector.   
     
     
         10 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by local administration. 
     
     
         11 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by topical administration. 
     
     
         12 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by systemic administration. 
     
     
         13 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by intravitreal, injection. 
     
     
         14 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by subtretinal injection. 
     
     
         15 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by intravitreal administration. 
     
     
         16 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by intracavity injection. 
     
     
         17 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by intraarterial administration. 
     
     
         18 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by intravenous administration. 
     
     
         19 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by intramuscular administration. 
     
     
         20 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by injection into tissue. 
     
     
         21 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by injection into gaps in tissue. 
     
     
         22 . The method of  claim 1 , wherein the substance is comprised in a preparation suitable for and/or administered by inhalation anal or nasal instillation. 
     
     
         23 . The method of  claim 1 , wherein the disease related with ocular neovascularization is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity (ROP), neovascular glaucoma or retinal vein occlusion.