Currently more than 100 million Americans and 1.5 billion people worldwide suffer from chronic pain. This is more than cancer, diabetes, and heart disease combined. Voltage-gated sodium channels are responsible for the transmission of pain signals. Nine genes have been identified, each having unique properties and tissue distribution patterns. Genetic studies have correlated a hereditary loss-of-function mutation in one human Na+ channel isoform ?Na?V?1.7 with a rare genetic disorder known as Congenital Insensitivity to Pain (CIP). Individuals with CIP are not able to feel pain without any significant secondary alteration. Thus, selective inhibition of ?Na?V?1.7 in normal humans could recapitulate the phenotype of CIP. However, the high homology of human ?Na?V 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 preliminary assays in mice). During this Phase I SBIR, we will 1) test additional pain targets ?in vitro?, and 2) evaluate the new targets ?in vivo ?in mice models of inflammatory and neuropathic pain. In addition, we will initiate our toxicology studies in mice. At the end of this Phase I work, we will know the spectrum of activity and safety of our optimized candidate to perform IND-enabling toxicology studies in Phase II.
Public Health Relevance Statement: Project Narrative Chronic pain affects more than 100 million people in the U.S. with over 25 million Americans living with daily chronic pain. Therapeutic options for these patients consist mainly of opioid narcotics, which come with side-effects and risk of addiction. Navega Therapeutics proposal aims to develop a non-addictive gene therapy for chronic pain, to improve the current paradigm of pain treatment.
Project Terms: addiction; Affect; alternative treatment; American; Antibodies; Behavioral; Binding; Biological Assay; Carrageenan; Chronic; Chronic inflammatory pain; chronic neuropathic pain; chronic pain; Chung model; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Computer Simulation; Congenital Pain Insensitivity; CRISPR/Cas technology; Data; Dependovirus; design; Development; Diabetes Mellitus; dosage; Drug or chemical Tissue Distribution; efficacy testing; epigenome; Family; Female; Formalin; gabapentin; Gene Targeting; gene therapy; Genes; Genetic study; Genome; Goals; Grant; Guide RNA; Health; Heart Diseases; Human; Human Genome; improved; In Vitro; in vivo; in vivo evaluation; Individual; inflammatory neuropathic pain; inflammatory pain; Inherited; inhibitor/antagonist; innovation; interest; Ligation; loss of function mutation; Malignant Neoplasms; member; Methods; Modality; Modeling; Molecular Conformation; Mononeuropathies; mouse genome; mouse model; Mus; Mutation; Narcotics; Neuropathy; non-opioid analgesic; novel; nuclease; Opioid; Outcome; Pain; Pain management; pain model; pain relief; pain signal; painful neuropathy; Pathway interactions; Patients; Pattern; Phase; Phenotype; Population; Property; Protein Isoforms; Proteins; rare genetic disorder; Repression; Risk; Safety; Sex Differences; side effect; Small Business Innovation Research Grant; small molecule inhibitor; Sodium Channel; spared nerve; Specificity; Spinal Ganglia; System; Testing; Therapeutic; tool; Toxicology; transmission process; Variant; voltage; Work
