Identification of genetic targets for modulation by oligonucleotides and generation of oligonucleotides for gene modulation

Abstract

Interative, preferably computer based iterative processes for generating synthetic compounds with desired physical, chemical and/or bioactive properties, i.e., active compounds, are provided. During iterations of the processes, a target nucleic acid sequence is provided or selected, and a library of candidate nucleobase sequences is generated in silico according to defined criteria. A “virtual” oligonucleotide chemistry is chosen and a library of virtual oligonucleotide compounds having the selected nucleobase sequences is generated. These virtual compounds are reviewed and compounds predicted to have particular properties are selected. The selected compounds are robotically synthesized and are preferably robotically assayed for a desired physical, chemical or biological activity. Active compounds are thus generated and, at the same time, preferred sequences and regions of the target nucleic acid that are amenable to oligonucleotide or sequence-based modulation are identified.

1 . A method comprising the steps of: 
 receiving from an input means an in silico oligomer;    receiving from said input means at least one prescribed property of the oligomer;    selecting a modification for generating a modified oligomer;    generating in silico the modified oligomer having the prescribed property and selected nucleobase modification; and    communicating the in silico modified oligomer to an output means.    
     
     
         2 . The method according to  claim 1  wherein the step of selecting the nucleobase modification is performed in silico by the computer.  
     
     
         3 . The method according to  claim 2  wherein the step of selecting the nucleobase modification is manually performed.  
     
     
         4 . The method according to  claim 1  wherein the input means is a computer.  
     
     
         5 . The method according to  claim 4  wherein the computer is connected to a network.  
     
     
         6 . The method according to  claim 5  wherein more than one computer is connected to the network.  
     
     
         7 . The method according to  claim 6  wherein the network is the internet.  
     
     
         8 . The method according to  claim 1  wherein the at least one prescribed property is a base chemistry.  
     
     
         9 . The method according to  claim 1  wherein the at least one prescribed property is a sugar chemistry.  
     
     
         10 . The method according to  claim 1  wherein the at least one prescribed property is a linker chemistry.  
     
     
         11 . The method according to  claim 1  wherein the at least one prescribed property is a conjugate.  
     
     
         12 . The method according to  claim 1  wherein the modification is a sugar modification.  
     
     
         13 . The method according to  claim 1  wherein the modification is a base modification.  
     
     
         14 . The method according to  claim 1  wherein the modification is a linker modification.  
     
     
         15 . The method according to  claim 1  wherein the modification is a conjugate modification.  
     
     
         16 . The method according to  claim 1  wherein the output means is a computer.  
     
     
         17 . The method according to  claim 1  wherein the output means is an automated synthesizer.  
     
     
         18 . A method comprising: 
 receiving from an input means an in silico oligomer to be synthesized having a prescribed property;    generating synthesis instructions adapted to a synthesizer; and    communicating the synthesis instructions to the synthesizer thereby providing the oligomer to be synthesized.    
     
     
         19 . The method according to  claim 18  wherein the input means is a computer.  
     
     
         20 . The method according to  claim 19  wherein the computer is connected to a network.  
     
     
         21 . The method according to  claim 20  wherein more than one computer is connected to the network.  
     
     
         22 . The method according to  claim 21  wherein the network is the internet.  
     
     
         23 . The method according to  claim 18  wherein the at least one prescribed property is a base chemistry.  
     
     
         24 . The method according to  claim 18  wherein the at least one prescribed property is a sugar chemistry.  
     
     
         25 . The method according to  claim 18  wherein the at least one prescribed property is a linker chemistry.  
     
     
         26 . The method according to  claim 18  wherein the at least one prescribed property is a conjugate.  
     
     
         27 . The method according to  claim 18  wherein the modification is a sugar modification.  
     
     
         28 . The method according to  claim 18  wherein the modification is a base modification.  
     
     
         29 . The method according to  claim 18  wherein the modification is a linker modification.  
     
     
         30 . The method according to  claim 18  wherein the modification is a conjugate modification.  
     
     
         31 . The method according to  claim 18  wherein the output means is a computer.  
     
     
         32 . The method according to  claim 18  where the output means is an automated synthesizer.  
     
     
         33 . A method comprising: 
 a) providing a group of properties which define a target oligomer and from which group a sub-group is selected;    b) receiving the selected sub-group of properties according to a user selection;    c) generating in silico, an oligomer having the selected sub-group of properties;    d) determining in silico, synthesis instructions for the oligomer of step c); and    e) communicating the synthesis instructions of step d) to a synthesizer.    
     
     
         34 . The method according to  claim 33  wherein the group of properties comprises a physical property and a thermodynamic property.  
     
     
         35 . The method according to  claim 33  wherein the oligomer is an oligonucleotide.  
     
     
         36 . The method according to  claim 33  wherein the synthesizer is an automated synthesizer.  
     
     
         37 . A method comprising: 
 receiving from an input means an in silico oligomer to be synthesized having a prescribed property, a threshold criteria, and a user defined target;    analyzing in silico the oligomer according to the prescribed property, the threshold criteria, and the target thereby producing an analysis report; and    communicating the analysis report to an output means.    
     
     
         38 . The method according to  claim 37  wherein the threshold criteria is a pass fail criteria based on a measure of proper synthetic outcome.  
     
     
         39 . The method according to  claim 38  wherein the 85% proper synthetic outcome is a pass.  
     
     
         40 . The method according to  claim 37  wherein the target is a nucleic acid.  
     
     
         41 . The method according to  claim 37  wherein the target is an RNA.  
     
     
         42 . The method according to  claim 37  wherein the analysis report provides applicability of the oligomer for an intended purpose.  
     
     
         43 . A method of selecting an oligomer from a library of oligomers according to user selection criterion comprising: 
 receiving a target through an input means according to a user selection;    receiving the user selection criterion, where the user criterion is a property selected from the group comprising; a chemical property, a physical property, and a biological property, wherein each property is in relation to the oligomer of the library of oligomers;    obtaining a threshold activity level and a test assay;    comparing a plurality of oligomers of the library to the target according to the test assay, thereby determining a rank for each compared oligomer of the library;    grouping in an active set the oligomers having rank greater than the threshold activity level; and    communicating the active set to an output means.    
     
     
         44 . The method according to  claim 43  wherein the target is a nucleic acid and the selection criteria is a chemical property.  
     
     
         45 . A method of designing an oligomer comprising: 
 receiving a target nucleic acid sequence;    receiving a defined criteria for at least one nucleobase of the oligomer;    receiving a prescribed set of properties comprising a physical property, a chemical property, or a biological property of the oligomer to be designed;    generating an oligomer design according to the prescribed set of properties and the target nucleic acid sequence;    generating in silico an oligomer according to the oligomer design; and    communicating said in silico oligomer to an output means.