Operational Techologies Corporation — Department of Health and Human Services SBIR Phase II: 300

Description

DESCRIPTION provided by applicant Development of Anti OLAM Aptamers as Novel Analgesics Phase The management of pain remains a major health care problem due to an incomplete understanding of pain mechanisms TRPV a prominent member of the transient receptor potential TRP family of ligand gated ion channels detects noxious chemical and physical stimuli in peripheral tissues Both pharmacological and gene deletion studies have demonstrated a pivotal role for TRPV in inflammatory heat hyperalgesia and other pain conditions Oxidized linoleic acid metabolites OLAMs have been recently demonstrated to comprise a novel family of endogenous TRPV agonists that contribute 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 Phase data provided herein demonstrate that injection of high affinity DNA aptamers developed against two of the major OLAMs HODE and HODE produced significant analgesia in patch clamp and rat behavioral models of heat pain Although these data provide evidence for proof of concept the aptamers must be developed into heavier conjugates in order to avoid rapid clearance by the kidneys and other major organs Accordingly Operational Technologies Corporation OpTech proposes to continue developing its successful high affinity anti OLAM aptamers from Phase into long lived aptamer conjugates in vivo which specifically bind to HODE and HODE and neutralize their pain producing activities for extended periods of time This would permit replacing anti HODE polyclonal antibodies with more specific less expensive and higher affinity DNA aptamers In Phase OpTech expects to complete several specific aims targeted toward enhancing pharmacokinetics PK by addition of ibuprofen to the andapos end ref thereby enabling association with serum albumin to add weight and retard renal and hepatic clearance Alternative but proven methods to slow in vivo clearance and protect aptamers in vivo including andapos polyethylene glycol PEG and covalent andapos rat albumin attachment will also be investigated Moreover dimensional molecular models of aptamer HODE interactions will be generated by the Southwest Research Institute SwRI to enable potential molecular engineering of improvements to aptamer affinity already exhibiting low nM KD values and specificity if possible using modified or unnatural deoxynucleotides In addition to in vitro patch clamp studies in the presence and absence of various doses of the aptamer conjugates rats will be studied for behavioral changes before and after injection and exposure to oC noxious heat with the various aptamer andapos conjugates If relatively long term on the order of hours PK is observed and heat burn analgesia can again be demonstrated OpTech will seek to file an IND or pre IND application with the FDA PUBLIC HEALTH RELEVANCE Development of Anti OLAM Aptamers as Novel Analgesics Phase Millions of patients suffer from pain and many available analgesic drugs andquot pain killersandquot suffer from either incomplete analgesia or unacceptable side effects This Phase SBIR proposal will further develop a novel class of long lived aptamer conjugate analgesics that work by blocking the endogenous capsaicin like substances that are released during tissue injury thereby specifically treating heat burn pain cancer pain and possibly counteracting some types of shock which are mediated by OLAMs oxidized linoleic acid metabolites including and hydroxyoctadecadienoic acid andquot HODEsandquot