Research Project
8306470
DESCRIPTION (provided by applicant): Development of Anti-OLAM Aptamers as Novel Analgesics The management of pain remains a major health care problem due to an incomplete understanding of pain mechanisms. TRPV1, a prominent member of the transient receptor potential (TRP) family of ligand-gated ion channel, detects noxious chemical and physical stimuli in peripheral tissues. Both pharmacological and gene deletion studies have demonstrated a pivotal role for TRPV1 in inflammatory heat hyperalgesia and other pain conditions. Oxidized linoleic acid metabolites (OLAMs) have been recently demonstrated to comprise a novel family of endogenous TRPV1 agonists that contributes to acute and inflammatory pain conditions. Therefore, compounds that block the OLAM system are likely to constitute a novel family of analgesics. In direct support of this prediction, preliminary data provided herein demonstrate that injection of antibodies against two of the major OLAMs, 9-HODE and 13-HODE, produce significant analgesia in two pain models. Although these data provide evidence for proof-of-concept, the clinical development of rabbit polyclonal antibodies is not feasible due to adverse effects related to immunogenicity. Accordingly, Operational Technologies Corporation (OpTech) proposes to use combinatorial aptamer chemistry to discover DNA aptamers that specifically bind to these OLAMs and neutralize their pain-producing activities. This would permit replacing antibodies with more specific, less expensive and perhaps higher affinity DNA aptamers. In Phase 1, OpTech expects to complete two overall Specific Aims. Aim 1 will develop, clone, and sequence several highly specific DNA aptamers that bind 9-hydroxydecadienoic acid (HODE) and 13-HODE without binding to the precursor lipid, linoleic acid (Fig 1A). Aim 2 will evaluate the analgesic activity of the aptamers using several in vivo preclinical rat models of pain. In Phase 2, OpTech will refine, optimize, and begin commercialization of its anti-OLAM aptamer compounds. The Phase 2 optimization process will include 3-D modeling of putative aptamer binding pocket interactions with the OLAMs. Based on 3-D modeling findings, OpTech anticipates adding modified bases having various functional groups (e.g., primary amines, methyl, thiol groups, etc.) that are now commercially available for addition to oligonucleotides at the point of chemical synthesis. The effects of these additional functional groups on aptamer-OLAM binding affinity are expected to better emulate amino acid side chains and will be studied by ELISA-like plate assays and surface plasmon resonance (SPR). The highest affinity and most specific unmodified or modified anti-OLAM aptamers will move into animal studies. The most effective aptamers in animal pain studies will be modified for longer in vivo lifetimes (3'-cholesterol addition and inclusion in liposomes, PEGylation, etc.) or time-released formulation and enter the FDA approval pipeline. PUBLIC HEALTH RELEVANCE: Development of Anti-OLAM Aptamers as Novel Analgesics Millions of patients suffer from pain and many available analgesic drugs (pain killers) suffer from either incomplete analgesia or unacceptable side-effects. The proposal will develop a novel class of analgesics that work by blocking the endogenous capsaicin-like substances that are released during tissue injury.
