Methods of identifying therapeutic compounds in a genetically defined setting

Abstract

The invention provides a method of identifying therapeutic compounds in a genetically defined setting. The method consists of contacting a cell indicative of a pathological condition from a diseased individual and a cell from a genetically related normal individual with a plurality of candidate therapeutic compounds under suitable assay conditions, and identifying a compound that preferentially alters a predetermined property of the cell from the diseased individual.

1 . A method of identifying a therapeutic compound potentially effective against a predetermined pathological condition, comprising:
 (a) contacting ex vivo a cell indicative of said pathological condition from a diseased individual with a plurality of candidate therapeutic compounds under suitable assay conditions;   (b) contacting ex vivo a control cell from a normal individual genetically related to said diseased individual with said plurality under said assay conditions, said genetically related normal individual having a common ancestor within 7 to 10 generations with said diseased individual, and   (c) identifying a compound from said plurality that preferentially alters one or more predetermined properties of said cell from said diseased individual, said compound being characterized as a therapeutic compound potentially effective against said pathological condition.   
     
     
         2 . The method of  claim 1 , wherein step (a) comprises contacting a cell from each of two or more genetically related diseased individuals. 
     
     
         3 . The method of  claim 2 , wherein said two or more genetically related diseased individuals exhibit a range of disease severity or risk. 
     
     
         4 . The method of  claim 1 , wherein step (b) comprises contacting a control cell from each of two or more genetically related normal individuals having a common ancestor within 7 to 10 generations with said diseased individual. 
     
     
         5 . The method of  claim 1 , wherein step (a) comprises contacting a cell from each of two or more genetically related diseased individuals and step (b) comprises contacting a control cell from each of two or more genetically related normal individuals having a common ancestor within 7 to 10 generations with said diseased individual. 
     
     
         6 . The method of  claim 1 , wherein said normal individual having a common ancestor within 7 to 10 generations with said diseased individual and said diseased individual are members of a genetically homogeneous population. 
     
     
         7 . The method of  claim 6 , wherein said genetically homogeneous population is an Icelandic population. 
     
     
         8 . The method of  claim 1 , wherein said plurality of candidate therapeutic compounds comprises greater than 10 5  compounds. 
     
     
         9 . The method of  claim 1 , wherein said plurality of candidate therapeutic compounds are sequentially contacted with said cell from said diseased individual or said control cell from said normal individual having a common ancestor within 7 to 10 generations with said diseased individual. 
     
     
         10 . The method of  claim 1 , wherein said plurality of candidate therapeutic compounds are sequentially contacted with said cell from said diseased individual and said control cell from said normal individual having a common ancestor within 7 to 10 generations with said diseased individual. 
     
     
         11 . The method of  claim 1 , wherein said plurality of candidate therapeutic compounds are simultaneously contacted with said cell from said diseased individual or said control cell from said normal individual having a common ancestor within 7 to 10 generations with said diseased individual. 
     
     
         12 . The method of  claim 1 , wherein said plurality of candidate therapeutic compounds are simultaneously contacted with said cell from said diseased individual and said control cell from said normal individual having a common ancestor within 7 to 10 generations with said diseased individual. 
     
     
         13 . The method of  claim 1 , wherein said pathological condition is selected from the group consisting of diseases of the cardiovascular system, nervous system, immune system, respiratory system, gastrointestinal system, endocrine system, and cancer. 
     
     
         14 . The method of  claim 1 , wherein said method is automated. 
     
     
         15 . The method of  claim 1 , wherein step (a) comprises contacting a cell from each of 10 or more genetically related diseased individuals. 
     
     
         16 . The method of  claim 1 , wherein step (a) comprises contacting a cell from each of 100 or more genetically related diseased individuals. 
     
     
         17 . The method of  claim 1 , wherein step (b) comprises contacting a control cell from each of 10 or more genetically related normal individuals. 
     
     
         18 . The method of  claim 1 , wherein step (b) comprises contacting a control cell from each of 100 or more genetically related normal individuals. 
     
     
         19 . The method of  claim 1 , wherein said plurality of candidate therapeutic compounds comprises greater than 50 compounds. 
     
     
         20 . The method of  claim 1 , wherein said pathological condition is cancer. 
     
     
         21 . The method of  claim 1 , wherein said predetermined property is selected from the group consisting of proliferation, adhesion, differentiation, motility and apoptosis. 
     
     
         22 . The method of  claim 1 , wherein said cell is obtained from a tissue selected from the group consisting of breast, prostate, colon, lung, brain and ovary. 
     
     
         23 . The method of  claim 1 , wherein said cell from said diseased individual is an unaffected cell. 
     
     
         24 . The method of  claim 1 , wherein said cell from said diseased individual and said cell from said normal individual are propagated in culture. 
     
     
         25 . The method of  claim 1 , wherein said cell from said diseased individual and said cell from said normal individual are transduced or transfected with a nucleic acid molecule. 
     
     
         26 . The method of  claim 1 , further comprising: (d) repeating steps (a) and (b) with said therapeutic compound obtained from step (c), and determining the ability of said therapeutic compound to preferentially alter a second or more predetermined property of said cell from said diseased individual.