Methods for Modulating the Efficacy of Nucleic Acid Based Therapies

Abstract

Covalently reactive antigen analogs are disclosed herein. The antigens of the invention may be used to stimulate production of catalytic antibodies specific for predetermined antigens associated with particular medical disorders. The antigen analogs may also be used to permanently inactivate endogenously produced catalytic antibodies produced in certain autoimmune diseases as well as in certain lymphoproliferative disorders. Also provided are methods for modulating the efficacy of nucleic acid based therapeutics.

1 . A method for modulating the efficacy of a nucleic acid based therapeutic comprising
 a) exposing said therapeutic to an agent under conditions suitable for a chemical reaction with said therapeutic, if any is present;   b) assessing whether said agent alters the molecular configuration of the nucleic acid based therapeutic or alters the attractive interaction between the therapeutic and the nucleic acid target;   said method further comprising providing a packaged pharmaceutical preparation of the nucleic acid based therapeutic to be administered wherein the instructions additionally include contraindication and adverse reaction information pertaining to agent(s) identified in step b) in the packaged pharmaceutical composition.   
     
     
         2 . The method as claimed in  claim 2 , wherein the reaction is a covalent reaction which causes a reduction in the binding energy of said nucleic acid based therapeutic to a target nucleic acid. 
     
     
         3 . The method as claimed in  claim 1 , wherein the agent is a polyunsaturated fatty acid, a congener or a metabolite of a polyunsaturated fatty acid. 
     
     
         4 . The method as claimed in  claim 1 , wherein the agent is selected from the group antramycin, ellipticine, or luzopeptin or their congeners or metabolites. 
     
     
         5 . The method as claimed in  claim 1 , where the nucleic acid based therapeutic is an oligonucleotide. 
     
     
         6 . The method as claimed in  claim 1 , where the nucleic acid based therapeutic is an antisense oligonucleotide, optionally comprising at least one modified backbone or nonstandard bases that are capable of forming double stranded molecular complexes. 
     
     
         7 . The method as claimed in  claim 1 , where the nucleic acid based therapeutic is a siRNA. 
     
     
         8 . The method as claimed in  claim 1 , wherein the nucleic acid based therapeutic is a gene expression vector. 
     
     
         9 . The method as claimed in  claim 1 , where the nucleic acid based therapeutic is a microRNA (miRNA) containing molecule. 
     
     
         10 . The method as claimed in  claim 1 , where the nucleic acid based therapeutic is an inhibitor of microRNA (miRNA). 
     
     
         11 . The method as claimed in  claim 1 , where the nucleic acid based therapeutic inhibits the expression of p53. 
     
     
         12 . The method as claimed in  claim 11 , where said therapeutic is an antisense oligonucleotide and inhibits the expression of p53. 
     
     
         13 . A method for modulating the efficacy of a nucleic acid based therapeutic by limiting exposure to an agent capable of alkylating one or more of bases of said therapeutic, said method comprising providing a packaged pharmaceutical preparation of the composition to be administered wherein the instructions additionally include contraindication and adverse reaction information pertaining to the packaged pharmaceutical composition. 
     
     
         14 . The method as claimed in  claim 13 , wherein co-administration of acetaminophen is contraindicated. 
     
     
         15 . The method as claimed in  claim 13 , wherein co-administration of a chemotherapeutic agent that directly or by means of a metabolite alkylates the adenine, guanine, cytosine, thymine or uracil in a nucleic acid based therapeutic is contraindicated. 
     
     
         16 . The method as claimed in  claim 15 , wherein the chemotherapeutic agent is selected from the group consisting of a platinum based compound, cisplatin, carboplatin, oxaliplatin, MGMT prodrug, temozolomide, DTIC, a nitrosourea compound, carmustine, lomustine, semustine, streptozocin, a nitrogen mustard, cyclophosphamide, CC-1065-duocarmycin, CC-1065, duocarmycin A, duocarmycin SA, yatakemycin, a sulfonylhydrazine prodrug, and cloretazine. 
     
     
         17 . The method as claimed in  claim 16 , wherein co-administration of an anti-infective agent is contraindicated. 
     
     
         18 . The method as claimed in  claim 16 , wherein the anti-infective is yatakemycin. 
     
     
         19 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is an oligonucleotide in a biologically compatible medium. 
     
     
         20 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is an antisense oligonucleotide optionally comprising at least one modified backbone with standard or nonstandard bases that are capable of forming double stranded molecular complexes. 
     
     
         21 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is a siRNA. 
     
     
         22 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is a gene expression vector. 
     
     
         23 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is a microRNA (miRNA) containing molecule. 
     
     
         24 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is an inhibitor of microRNA (miRNA). 
     
     
         25 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic inhibits the expression of p53. 
     
     
         26 . The method as claimed in  claim 13 , where the nucleic acid based therapeutic is an antisense oligonucleotide which inhibits the expression of p53. 
     
     
         27 . A method for modulating the efficacy of a nucleic acid based therapeutic by controlling for exposure to acetaminophen, said method comprising providing a packaged pharmaceutical preparation of the composition to be administered wherein the instructions additionally include contraindication and adverse reaction information pertaining to the packaged Pharmaceutical Composition. 
     
     
         28 . The method as claimed in  claim 27 , wherein co-administration of acetaminophen is contraindicated. 
     
     
         29 . The method as claimed in  claim 27 , wherein co-administration of acetaminophen is contraindicated as it results in the production of a metabolite, NAPQI which covalently interacts with and inhibits the activity of the nucleic based therapeutic. 
     
     
         30 . The method of  claim 27 , wherein said nucleic acid-based therapeutic comprises an oligonucleotide. 
     
     
         31 . The method of  claim 27 , wherein said nucleic acid-based therapeutic comprises an deoxyribo-oligonucleotide or a ribo-oligonucleotide. 
     
     
         32 . The method of  claim 31 , wherein said oligonucleotide is between at least 10 and 40 bases in length. 
     
     
         33 . The method of  claim 32 , wherein said oligonucleotide is an antisense. 
     
     
         34 . The method of  claim 32 , wherein said oligonucleotide is an aptamer. 
     
     
         35 . The method of  claim 32 , wherein said oligonucleotide is an immunomodulator. 
     
     
         36 . The method of  claim 32 , wherein said oligonucleotide is forms a triple helix with DNA. 
     
     
         37 . The method of  claim 32 , wherein said nucleic acid based therapeutic is an oligonucleotide and has a backbone structure selected from the group consisting of at least one of phosphorothioate, methyl phosphonate, morpholino, phosphoramidate, dithioate, ethylphosphonate, piperazine or modified versions of any of these backbones. 
     
     
         38 . The method of  claim 37 , wherein said modifications involve pegylation, addition of terminal 5′-tocopheryl or 3′-tocopheryl or 2′O-methyl, 2′-O-propyl, or 2′-O-(2-methyoxy)ethyl modifications. 
     
     
         39 . The method of  claim 37 , wherein said modifications are to a phosphorothioate backbone. 
     
     
         40 . The method of  claim 37  wherein said antisense molecule has a high GC content (≧60%) to ensure a high melting point with the target nucleic acid. 
     
     
         41 . A method for inhibiting the action of a nucleic acid based therapeutic comprising administering an effective amount of acetaminophen to a patient in need thereof, such that reactive intermediates are formed which inactivate said therapeutic. 
     
     
         42 . The method of  claim 41  for reduction in side effects associated with administration of nucleic acid based therapies, said side effects involve tissues that express cytochrome P450 including but not limited to liver, kidneys bone marrow, blood cells, gastrointestinal tract, lung, adrenals and CNS. 
     
     
         43 . The method of  claim 40 , wherein the therapeutic inhibits p53. 
     
     
         44 . The method of  claim 40 , wherein the therapeutic is an antisense oligonucleotide that inhibits p53 expression. 
     
     
         45 . The method of  claim 40 , wherein the therapeutic is an antisense oligonucleotide that alters the splicing of p53 pre-RNA. 
     
     
         46 . The method of  claim 40 , wherein the therapeutic is an agent selected from the group consisting of an siRNA, microRNA (miRNA), an inhibitor of microRNA (miRNA), and a genetic expression vector. 
     
     
         47 . A method for increasing the efficacy of nucleic acid-based therapy comprising administering a composition comprising a therapeutic amount of a nucleic acid based therapeutic to a human in need thereof, while excluding the administration of acetaminophen to said human so that the nucleic acid molecule and acetaminophen are not present in the human in vivo at the time the nucleic acid based therapeutic is producing its therapeutic effect. 
     
     
         48 . A method of determining the efficacy of a pharmaceutical composition comprising detecting the presence or absence of N-acetyl-p-benzoquinone immune (NAPQI) in a biological sample, wherein the presence of NAPQI correlates with reduced efficacy of the pharmaceutical composition. 
     
     
         49 . A method for identifying biochemical interactions which modulate the efficacy of nucleic acid based therapeutics in vivo comprising:
 a) contacting said therapeutic with an agent which is capable of reacting with said nucleic acid based therapeutic;   b) assessing whether said agent alters the molecular configuration of the nucleic acid based therapeutic or alters the attractive interaction between the therapeutic and the nucleic acid target, agents so identified which reduce the efficacy of said nucleic acid based therapeutic being contraindicated in patients being treated with said nucleic acid based therapeutic.   
     
     
         50 . The method of  claim 49 , wherein said agent forms a covalent bond with said therapeutic. 
     
     
         51 . The method of  claim 49  wherein said agent alters the molecular configuration of the nucleic acid based therapeutic.