R2R1/2 In Diagnosis and Therapy

Abstract

The present invention stems from the finding that two genes designated R2R 1 and R2R 2 , play important roles in tissue development and cancer biology. In particular, the inventors have discovered that these two genes are expressed in pulmonary cells and are required for late branching morphogenesis of pulmonary epithelium and endothelium and support the development/maintenance of the refined three dimensional architecture of the lung. These genes are essential in the squamous differentiation program and development/maintenance of the progenitor (Krt14 expressing) cell pool. Moreover, the inventors have identified crucial roles for these genes in cancer biology, particularly processes associated with the acquisition of an immortal and metastatic phenotype (including cancer progression and metastasis) and pulmonary and cardiac development. Accordingly, the invention provides compounds and methods for use in the treatment of cardiac and pulmonary diseases and well as in cancer.

1 - 12 . (canceled) 
     
     
         13 . An antibody or antigen binding fragment thereof capable of binding to an R2R 1/2  protein or a fragment thereof. 
     
     
         14 . The antibody of  claim 13 , wherein the R2R 1/2  protein is encoded by a sequence selected from the group consisting of those designated SEQ ID NOS: 3, 6, 9 and 12, or a sequence at least 60% identical thereto. 
     
     
         15 . A method of treating one or more diseases and/or conditions selected from the group consisting of:
 (a) cardiac diseases and/or conditions;   (b) pulmonary diseases and/or conditions; and   (c) cancer;   
       said method comprising administering a therapeutically effective amount of:
 (i) a polynucleotide comprising an R2R 1/2  gene, wherein the R2R 1/2  gene is encoded by a sequence selected from the group consisting of those designated SEQ ID NOS: 1, 2, 4, 5, 7, 8, 10 and 11, or a sequence at least 60% identical thereto; 
 (ii) a polypeptide comprising an R2R 1/2  protein, wherein the R2R 1/2  protein is encoded by a sequence selected from the group consisting of those designated SEQ ID NOS: 3, 6, 9 and 12 or a sequence at least 60% identical thereto; 
 (iii) an antisense oligonucleotide capable of modulating the expression of an R2R 1/2  gene; 
 (iv) the antibody of  claim 13 ; or 
 (v) the antibody of  claim 13 , wherein the R2R 1/2  protein is encoded by a sequence selected from the group consisting of those designated SEQ ID NOS: 3, 6, 9 and 12, or a sequence at least 60% identical thereto; 
 
       to a subject in need thereof. 
     
     
         16 . A method of diagnosing one or more diseases and/or conditions selected from the group consisting of:
 (a) a cardiac disease and/or condition;   (d) a pulmonary disease and/or condition;   (c) cancer; and   (d) a susceptibility or predisposition to any of (a) to (c);   said method comprising the step of detecting a level of R2R 1  and/or R2R 2  gene expression in a sample provided by a subject to be tested, wherein detection of an aberrant level of the R2R 1  and/or R2R 2  gene in said sample, is indicative of one or more of the diseases and/or conditions provided as (a)-(c) above and/or a susceptibility or predisposition thereto.   
     
     
         17 . The method of  claim 16 , wherein the method comprises the use of an oligonucleotide probe and/or primer designed to hybridise under stringent conditions to all or part of a sequence selected from the group consisting of SEQ ID NOS: 1; 2; 4; 5; 7; 8; 10 and 11. 
     
     
         18 . A method of identifying or obtaining agents which modulate the expression of an R2R 1  and/or R2R 2  genes, said method comprising the steps of contacting the R2R 1  and/or R2R 2  genes with a test agent and detecting any modulation of R2R 1/2  gene expression. 
     
     
         19 . A pharmaceutical composition comprising (i) an R2R 1/2  gene provided by SEQ ID NOS: 1, 2, 4, 5, 7, 8, 10 or 11, or a sequence at least 60% identical thereto, in association with a pharmaceutically acceptable excipient, carrier or diluent; or (ii) an R2R 1/2  protein provided by SEQ ID NOS: 3, 6, 9 and 12, or a sequence at least 60% identical thereto, in association with a pharmaceutically acceptable excipient, carrier or diluent. 
     
     
         20 . An animal model for the study of a cardiac and/or pulmonary disease or condition, or cancer, wherein the animal model has been generated by modulation or disruption of an R2R 1/2  gene.