The goal of this project is design and optimize a gene therapy product that relieves pain in a non-permanent, non-addictive and long lasting manner. There are more than 100 million Americanssuffering from chronic pain and current treatments consist mainly of opioid narcotics. However,opioids have severe side effects and are highly addictive. Voltage-gated sodium channelstransmit pain signals in nociceptive neurons. Genetic studies have correlated a rare hereditaryloss-of-function mutation in one channel isoform (NaV1.7) with a rare genetic disorder known asCongenital Insensitivity to Pain (CIP). Thus, selective repression of NaV1.7 could recapitulate thephenotype of CIP. However, the high homology of human NaV proteins, have frustrated mostefforts to develop selective inhibitors. We have developed an innovative gene therapy approachto target NaV1.7 in vivo, and have demonstrated its efficacy in three murine models of pain. Duringthis Phase I SBIR, we will optimize this gene therapy to target the human NaV1.7 sequence inhuman cell lines, and then we will choose the best designs to test them in human DRG neuronsfor potency, specificity, and efficacy in an ex vivo chemotherapy-induced neuropathic pain model.Thus, Navega's final goal is to develop novel therapeutics that can mitigate pain through the useof specific gene therapy approaches to provide an alternative treatment to opioids for chronicpain.
Public Health Relevance Statement: Project Narrative
According to the CDC, 8.0% of U.S. adults (19.6 million) suffer from high-impact chronic
pain. Therapeutic options for these patients consist mainly of opioid narcotics, which come
with side-effects and the risk of addiction. Based on our preclinical data in rodents, Navega
Therapeutics' proposal aims to optimize a gene therapy for chronic pain in human cell
lines and human dorsal root ganglion neurons.
Project Terms: Dependovirus ; Adeno-Associated Viruses ; Dependoparvovirus ; adeno associated virus group ; Adult ; 21+ years old ; Adult Human ; adulthood ; Affect ; Pain management ; Pain Control ; Pain Therapy ; pain treatment ; Congenital Pain Insensitivity ; Congenital Analgesia ; Congenital Pain Indifference ; Congenital Pain Indifferences ; congenital hyposensitivity to pain ; congenital insensitivity to pain ; familial hyposensitivity to pain ; familial insensitivity to pain ; inhibitor/antagonist ; inhibitor ; Antibodies ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biotechnology ; Biotech ; Western Blotting ; Western Immunoblotting ; protein blotting ; Calcium ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Centers for Disease Control and Prevention (U.S.) ; CDC ; Centers for Disease Control ; Centers for Disease Control and Prevention ; United States Centers for Disease Control ; United States Centers for Disease Control and Prevention ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Electrophysiology (science) ; Electrophysiology ; Neurophysiology / Electrophysiology ; electrophysiological ; Environment ; Future ; Spinal Ganglia ; Dorsal Root Ganglia ; dorsal root ganglion ; gene therapy ; DNA Therapy ; Gene Transfer Clinical ; Genetic Intervention ; gene-based therapy ; genetic therapy ; genomic therapy ; Genes ; Goals ; Health ; Human ; Modern Man ; In Vitro ; Methods ; Molecular Conformation ; Molecular Configuration ; Molecular Stereochemistry ; conformation ; conformational state ; Mus ; Mice ; Mice Mammals ; Murine ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Narcotics ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Pain ; Painful ; Patients ; Phenotype ; Protein Engineering ; genetic protein engineering ; protein design ; Proteins ; Repression ; Research Personnel ; Investigators ; Researchers ; Risk ; Rodent ; Rodentia ; Rodents Mammals ; Sodium Channel ; Sodium Ion Channels ; Specificity ; Streptococcus pyogenes ; S pyogenes ; S. pyogenes ; Streptococcus Group A ; Testing ; Translating ; Measures ; Zinc Fingers ; Zinc Finger Domain ; Zinc Finger Motifs ; Guide RNA ; gRNA ; Businesses ; Paclitaxel ; Anzatax ; Asotax ; Bristaxol ; Paclitaxel (Taxol) ; Praxel ; Taxol ; Taxol A ; Taxol Konzentrat ; chronic pain ; Treatment Failure ; therapy failure ; base ; Phase ; Variant ; Variation ; Nociception ; nociceptive ; Opioid ; Opiates ; Therapeutic ; Genetic ; electric field ; Hereditary ; Inherited ; System ; American ; Isoforms ; Protein Isoforms ; voltage ; Human Cell Line ; Modeling ; drug development ; Molecular Interaction ; Binding ; Ortholog ; Orthologous Gene ; Data ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Development ; developmental ; Image ; imaging ; pre-clinical ; preclinical ; painful neuropathy ; neuropathic pain ; vector ; design ; designing ; loss of function mutation ; innovation ; innovate ; innovative ; chemotherapy ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; cellular transduction ; cell transduction ; transduced cells ; addiction ; addictive disorder ; alternative treatment ; genome-wide ; genome scale ; genomewide ; transcriptome sequencing ; RNA Seq ; RNA sequencing ; RNAseq ; Genetic study ; CRISPR/Cas technology ; CRISPR method ; CRISPR methodology ; CRISPR technique ; CRISPR technology ; CRISPR-CAS-9 ; CRISPR-based method ; CRISPR-based technique ; CRISPR-based technology ; CRISPR-based tool ; CRISPR/Cas method ; CRISPR/Cas9 ; CRISPR/Cas9 technology ; Cas nuclease technology ; Clustered Regularly Interspaced Short Palindromic Repeats method ; Clustered Regularly Interspaced Short Palindromic Repeats methodology ; Clustered Regularly Interspaced Short Palindromic Repeats technique ; Clustered Regularly Interspaced Short Palindromic Repeats technology ; small molecule inhibitor ; clinical translation ; pain model ; chronic pain patient ; patient with chronic pain ; pain relief ; relieve pain ; pain signal ; single-cell RNA sequencing ; scRNA-seq ; single cell RNA-seq ; single cell RNAseq ; in vivo evaluation ; in vivo testing ; rare genetic disorder ; rare genetic disease ; side effect ;
