Inhibition of endosomal toll-like receptor activation
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.
1. A method of inhibiting nucleic acid-induced activation of toll-like receptor 3 (TLR3) or toll-like receptor 9 (TLR9) to treat a TLR3 or TLR9 induced inflammatory or immune response comprising administering to a patient in need of said inhibition of nucleic acid-induced activation of TLR3 or TLR9 an agent that binds a nucleic acid responsible for said induction of activation in an amount and under conditions such that said inhibition of said activation is effected, wherein the agent is poly(amidoamine) (PAMAM).
2. 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.
3. The method of claim 1 , further comprising exposing the patient to a nucleic acid prior to administering the agent.
4. The method of claim 1 , wherein the patient was exposed to a nucleic acid prior to administration of the agent.
5. The method of claim 4 , wherein the nucleic acid is pathogen-derived or is released from dead or damaged cells of the patient.
6. The method of claim 1 , further comprising detecting the inhibition of activation of TLR3 or TLR9 by measuring TNF-α or IL-6 production in the patient.
7. The method of claim 1 , further comprising detecting the inhibition of activation of TLR3 or TLR9 by measuring CD86 expression.
8. The method of claim 1 , wherein administration of the agent results in a reduction in the acute inflammatory response in the patient.
9. The method of claim 1 , wherein the agent does not affect lipopolysaccharide-mediated inflammation.
10. The method of claim 1 , wherein the patient suffers from a disease selected from the group consisting of an infectious disease, a cardiovascular disease, cancer bacterial sepsis, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, chronic obstructive pulmonary disease, obesity and psoriasis.