Inhibition of endosomal toll-like receptor activation

Abstract

The present invention relates, in general, to pattern-recognition receptors (PRRs), including toll-like receptors (TLRs), and, in particular, to a method of inhibiting nucleic acid-induced activation of, for example, endosomal TLRs using an agent that binds to the nucleic acid (“nucleic acid binding agent”), preferably, in a manner that is independent of the nucleotide sequence, the chemistry (e.g., DNA or RNA, with or without base or sugar modifications) and/or the structure (e.g., double-stranded or single-stranded, complexed or uncomplexed with, for example protein) of the nucleic acid(s) responsible for inducing TLR activation. The invention also relates to methods of identifying nucleic acid binding agents suitable for use in such methods.

What is claimed is: 
     
         1 . A method of inhibiting nucleic acid-induced activation of a pattern recognition receptor (PRR) comprising administering to a patient in need thereof an agent that binds a nucleic acid responsible for said induction of activation in an amount and under conditions such that inhibition of said activation is effected. 
     
     
         2 . The method according to  claim 1  wherein said PRR is an endosomal toll-like receptor (TLR) or a cytoplasmic PRR. 
     
     
         3 . The method according to  claim 1  wherein said agent binds said nucleic acid in a manner that is independent of nucleotide sequence, chemistry or structure. 
     
     
         4 . The method according to  claim 1  wherein said agent is a positively charged compound. 
     
     
         5 . The method according to  claim 4  wherein said compound is a protein, polypeptide, peptide, lipid or natural or synthetic polymer. 
     
     
         6 . The method according to  claim 5  wherein said compound is a protein, polypeptide or peptide. 
     
     
         7 . The method according to  claim 6  wherein said compound is a protamine, a DNA or RNA reactive antibody, a heterogeneous nuclear ribonucleoprotein, a chimeric peptide, or a viral protein that packages DNA or RNA. 
     
     
         8 . The method according to  claim 5  wherein said compound is a cationic lipid. 
     
     
         9 . The method according to  claim 8  wherein said cationic lipid is linear poly(ethyleneimine) (PEI), poly(L-lysine) (PLL), poly(amidoamine) (PAMAM) dendrimer generation 4, chitosan, DOTMA, DOTAP, DMRIE, DOTIM, DOGS, DC-Chol, BGTC or DOPE. 
     
     
         10 . The method according to  claim 1  wherein said agent is an intercalating agent or a porphyrin. 
     
     
         11 . The method according to  claim 1  wherein said agent is polycationic polymer. 
     
     
         12 . The method according to  claim 11  wherein said polycationic polymer is CDP, CDP-im, PPA-DPA, PAMAM or HDMBr. 
     
     
         13 . A method of controlling an autoimmune or inflammatory response comprising administering to a patient in need thereof an agent that binds a nucleic acid responsible for said response in an amount and under conditions such that said response is controlled. 
     
     
         14 . The method according to  claim 13  wherein said nucleic acid is pathogen derived or released from a dead or damaged cell of said patient. 
     
     
         15 . The method according to  claim 14  wherein said patient suffers from an infectious disease, a cardiovascular disease, cancer, bacterial sepsis, multiple sclerosis, systemic lupus erythematosis, rheumatoid arthritis, COPD, obesity or psoriasis. 
     
     
         16 . A method of preventing the induction of, or inhibiting the progression of, a thrombotic disorder comprising administering to a patient in need thereof an agent that binds a nucleic acid responsible for said induction or progression in an amount and under conditions such that said prevention or inhibition is effected. 
     
     
         17 . A method of identifying a candidate nucleic acid binding agent suitable for use in the method according to  claim 1  comprising:
 i) culturing PRR-containing cells with a first PRR agonist in the presence and absence of a test agent, 
 ii) obtaining a supernatant sample from said culture of step (i), 
 iii) analyzing said sample for the presence of a product of an intracellular signaling event initiated by PRR activation, and 
 iv) repeating steps (i)-(iii) with second PRR agonist having a sequence, chemistry or structure different from that of the first agonist, 
 wherein a test agent that inhibits PRR agonist activation in a manner independent of sequence, chemistry or structure of the PRR agonist used is a candidate nucleic acid binding agent.