Regulators of NaV Channels Novel Anti Allodynic Drug Candidates

PROJECT SUMMARY Chemotherapy induced peripheral neuropathy CIPN is a common prevalence and potentially dose limiting side effect of many cancer chemotherapy drug treatment regimens Clinically CIPN presents with pain that is burning shooting or electric shock like The increase in prevalence of cancer coupled with an increase in the cancer survival rates due to chemotherapy regimens is transforming cancer pain into a large unmet medical problem Neurotoxic chemotherapeutic agents e g antimicrotubule agents like paclitaxel may cause structural damage to peripheral nerves resulting in aberrant somatosensory processing in the peripheral and or central nervous system Dorsal root ganglia DRG sensory neurons as well as neuronal cells in the spinal cord are the preferential sites in which chemotherapy induced neurotoxicity occurs Pathogenesis is complex but includes alterations in ion channels and ectopic activation of nociceptors For example paclitaxel induced chemotherapy increases the excitability of DRG neurons with a commensurate increase in NaV a voltage gated sodium channel NaV is expressed in both large and small diameter DRG neurons and in most functionally identified nociceptors Of the nine Na channel isoforms NaV plays a key role in setting the threshold for action potential generation in primary sensory neurons Genetic and functional studies have established NaV as a major contributor to pain signaling in humans NaV has been difficult to target selectively over other voltage gated sodium channels due to high sequence similarity between isoforms Therefore alternative approaches are still needed for developing drugs targeting NaV Regulonix LLCandapos s approach has the potential to be a paradigm shift because we are targeting NaV indirectly by focusing on a signaling pathway that controls surface expression and activity of this channel From the calcium channel pain therapeutics literature it is clear that no one drug is efficacious in relieving pain in all patients Whether this also holds true for current NaV drugs is an open question Thus development of a `thirdandapos generation of NaV inhibitors such as the Regulators of NaV channels i e ReNs proposed here is needed Regulonix objectives in this STTR are to identify ReNs that exhibit more efficacious and safer profiles than current drugs for CIPN and that display extended durations of action Doing so allows for a phase II STTR application for the IND enabling studies of a selected ReN Regulonixandapos s specific aims are To elucidate channel specificity and biophysical properties of select ReNs to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells To validate the drug properties of optimized ReNs both in vitro and in vivo and to identify optimized ReNs for preclinical efficacy using a pain model CIPN and determine neurological side effects motor impairment memory weight gain and smell that provide information about efficacy and functional toxicity At the conclusion of our study we expect to have a validated ReN and worthy backup compounds NARRATIVE Regulonix LLC proposes to develop novel small molecules regulators ReNs to indirectly target the NaV voltage gated sodium channel a key channel in pathogenesis of neuropathic pain including chemotherapy induced peripheral neuropathy CIPN ReNs will be tested in a neurotoxicity model rotarod and cellular pharmacological assays that provide information about efficacy and function Next channel specificity and biophysical properties of select ReNs will be elucidated to gain mechanistic and safety information and to document the unique pathway for function in relevant neuronal cells including human neurons Finally drug properties of an optimized ReN and its oral effectiveness will be determined in the paclitaxel model of CIPN