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Regulators of NaV Channels Novel Anti Allodynic Drug Candidates

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1R41CA210857-01A1
Agency Tracking Number: R41CA210857
Amount: $299,999.00
Phase: Phase I
Program: STTR
Solicitation Topic Code: 102
Solicitation Number: PA16-303
Solicitation Year: 2016
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-05-01
Award End Date (Contract End Date): 2018-04-30
Small Business Information
Tucson, AZ 85718-5824
United States
DUNS: 080053231
HUBZone Owned: No
Woman Owned: Yes
Socially and Economically Disadvantaged: No
Principal Investigator
 (520) 626-4281
Business Contact
Phone: (520) 271-0433
Research Institution
PO BOX 210158, ROOM 510
TUCSON, AZ 85721-0158
United States

 Nonprofit college or university

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

* Information listed above is at the time of submission. *

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