Treatment of Chemotherapy-Induced Peripheral Neuropathy via Genetic Repression of Sodium Channels - Project Summary/Abstract
The goal of this project is to develop a therapeutic product that relieves chemotherapy-induced
peripheral neuropathy (CIPN) in a non-permanent, non-addictive and long lasting manner to
improve the quality of life of cancer patients. Currently more than 100 million Americans and 1.5
billion people worldwide suffer from chronic pain. Voltage-gated sodium channels transmit pain
signals in nociceptive neurons. Nine genes have been identified, each having unique properties
and tissue distribution patterns. Genetic studies have correlated a rare hereditary loss-of-function
mutation in one channel isoform – NaV1.7 – with a genetic disorder known as Congenital
Insensitivity to Pain (CIP). Individuals with CIP are not able to feel pain whatsoever and they do
not present any significant secondary alteration. Thus, selective repression of NaV1.7 should
recapitulate the phenotype of CIP. However, the high homology of human NaV proteins, have
frustrated most efforts to develop selective inhibitors. We have developed a non-permanent gene
therapy to target pain that is non-addictive (because it targets a non-opioid pathway), highly
specific (only targeting the gene of interest), and long-term lasting (around 3 weeks in our
preliminary assays in mice). During this Phase I SBIR, we will 1) optimize the in vitro targeting of
NaV1.7 along with targeting NaV1.8 and NaV1.9, since these channels are also responsible for the
transmission of pain signals, 2) evaluate the new targets in vivo in a chemotherapy-induced
peripheral neuropathy (CIPN) model and determine whether there are any sex differences in
efficacy of the therapeutic, and 3) perform preliminary safety and toxicology studies in mice. At
the end of Phase I, we will know the potency, specificity, and safety of our optimized gene therapy
and will apply for a Phase II SBIR grant to perform IND-enabling toxicology studies. Our goal is
to advance this therapy forward into the clinic, to provide an alternative treatment to opioids for
cancer patients in pain.
