SBIR-STTR Award

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.

Public Health Relevance Statement:


Project narrative:
Navega Therapeutics' proposal aims to investigate the contribution of NaV1.7, NaV1.8 and NaV1.9 voltage-gated sodium channels in the pain induced by chemotherapeutic agents. This study will improve our understanding of the mechanisms underlying voltage-gated sodium channels in chemotherapy-induced peripheral neuropathy and may lead to promising candidates to improve the quality of life of cancer survivors.

Project Terms:
Dependovirus; adeno associated virus group; Dependoparvovirus; Adeno-Associated Viruses; Affect; Pain management; pain treatment; Pain Therapy; Pain Control; Congenital Pain Insensitivity; familial insensitivity to pain; familial hyposensitivity to pain; congenital insensitivity to pain; congenital hyposensitivity to pain; Congenital Pain Indifferences; Congenital Pain Indifference; Congenital Analgesia; inhibitor/antagonist; inhibitor; Antibodies; Biological Assay; Biologic Assays; Bioassay; Assay; cis-Platinum; cis-Dichlorodiammineplatinum(II); cis-Diamminedichloroplatinum(II); cis-Diamminedichloroplatinum; cis-Diaminedichloroplatinum; cis platinum compound; cis dichlorodiammineplatinum; Platinum Diamminodichloride; Peyrone's Salt; Peyrone's Chloride; Dichlorodiammineplatinum; Cysplatyna; Cisplatinum; Cisplatina; Cis-platinum II Diamine Dichloride; Cis-platinum II; Cis-platinous Diamine Dichloride; Cis-dichloroammine Platinum (II); Cis-diamminedichloro Platinum (II); Cis-diamminedichloridoplatinum; Cis-diammine-dichloroplatinum; CDDP; Cisplatin; multi-modal treatment; multi-modal therapy; combined treatment; combined modality treatment; combination therapy; Multimodal Treatment; Multimodal Therapy; Combined Modality Therapy; Family; Female; dorsal root ganglion; Dorsal Root Ganglia; Spinal Ganglia; genomic therapy; genetic therapy; gene-based therapy; Genetic Intervention; Gene Transfer Clinical; DNA Therapy; gene therapy; Genes; Genome; human whole genome; Human Genome; Goals; Grant; Health; Modern Man; Human; Allergy; Hypersensitivity; In Vitro; heavy metal lead; heavy metal Pb; Pb element; Lead; Methods; conformational state; conformation; Molecular Stereochemistry; Molecular Configuration; Molecular Conformation; Murine; Mice Mammals; Mice; Mus; genome mutation; Genetic defect; Genetic Change; Genetic Alteration; Mutation; neuronal; Neurocyte; Neural Cell; Nerve Unit; Nerve Cells; Neurons; Loss of Sensation; Numbness; Painful; Pain; Patients; Peripheral Neuropathy; Peripheral Nervous System Disorders; Peripheral Nerve Diseases; PNS Diseases; Peripheral Nervous System Diseases; Phenotype; Proteins; QOL; Quality of life; Repression; Risk; Safety; Sodium Ion Channels; Sodium Channel; Specificity; Testing; Tissue Distribution; Drug or chemical Tissue Distribution; Toxicology; Neurontin; gabapentin; gRNA; Guide RNA; chronic pain; base; dosage; improved; Phase; Variant; Variation; Nociception; nociceptive; inflammatory pain; Individual; Opioid; Opiates; Gene Targeting; non-opioid analgesic; nonopioid; nonopiate analgesic; non-opioid; non-opiate analgesic; non-narcotic analgesic; Nonopioid Analgesics; Nonnarcotic Analgesics; Therapeutic; Genetic; Inherited; Hereditary; Clinic; Pattern; System; interest; American; cancer pain; nuclease; Protein Isoforms; Isoforms; voltage; novel; member; Modality; chemotherapeutic agent; Modeling; Property; Molecular Interaction; Binding; Dose; Data; in vivo; Cancer Patient; Cancer Survivor; survive cancer; Small Business Innovation Research Grant; Small Business Innovation Research; SBIR; transmission process; Transmission; Development; developmental; Pathway interactions; pathway; design; designing; Treatment Efficacy; therapy efficacy; therapeutically effective; therapeutic efficacy; intervention efficacy; Outcome; Population; loss of function mutation; innovation; innovative; innovate; Early treatment; early therapy; mouse genome; chemotherapy; mouse model; murine model; addiction; addictive disorder; alternative treatment; effective therapy; effective treatment; efficacy testing; epigenome; Clustered Regularly Interspaced Short Palindromic Repeats; CRISPR/Cas system; CRISPR; Genetic study; Chemotherapy-induced peripheral neuropathy; CRISPR/Cas technology; Cas nuclease technology; CRISPR/Cas9 technology; CRISPR/Cas9; CRISPR/Cas method; CRISPR-based tool; CRISPR-based technology; CRISPR-based technique; CRISPR-based method; CRISPR-CAS-9; CRISPR technology; CRISPR technique; CRISPR methodology; CRISPR method; small molecule inhibitor; pain model; pain relief; relieve pain; pain signal; Genetic Diseases; genetic disorder; genetic condition; in vivo evaluation; in vivo testing; side effect; Sex Differences; sex-specific differences; sex-related differences; sex-dependent differences

The goal of this project is to develop a gene therapy 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. Current management of CIPN and cancer pain is very poor, with 1 in 3 patients not receiving pain medication considered appropriate for the intensity of pain experienced. With the limited efficacious treatment options available, opioids are often prescribed, however these can lead to addiction. We are in urgent need of novel pain therapies that would alleviate the side effects of opioids. Voltage- gated sodium channels (NaV family) have been used in nociceptive transmission and contribution to the hyperexcitability in primary afferent nociceptive neurons. Additionally, many chemotherapy agents induce ion channel expression including NaV1.7 and NaV1.8, leading to CIPN. Hence, these sodium channels have been attractive targets for developing chronic pain therapies. However, the high homology of human NaV proteins has frustrated most efforts to develop selective protein inhibitors. Instead of targeting the protein, Navega proposes to develop a non-permanent epigenome regulation tool to target pain. This novel approach is non-addictive, highly specific, and long-lasting. During Phase I, we determined that the simultaneous inhibition of NaV1.7 and NaV1.8, was more efficacious at reversing CIPN than repressing each channel alone. We also demonstrated the safety of our approach at doses tested in mice. During Phase II we will: 1) perform dose-range studies in mice to determine the therapeutic window; 2) optimize our reagents to target the human genome; and 3) perform GLP definitive safety studies in NHPs. We will prepare an IND application to the FDA, and will submit it at the end of the Phase II project. Our final goal is to develop novel therapeutics that can mitigate CIPN through the use of a specific gene therapy approach that can simultaneously target two voltage gated sodium channels (something not possible with small molecules) and provide an alternative treatment to opioids for patients with chronic pain.

Public Health Relevance Statement:


Project narrative:
Pain presents a major societal problem, and current pain therapeutics exhibit limited efficacy, unwanted side effects and the potential for drug abuse and diversion. Navega Therapeutics' proposal aims to develop a precision medicine drug able to inhibit two targets simultaneously: NaV1.7 and NaV1.8. This gene therapy has the potential to change the current paradigm of severe pain management.

Project Terms:
Dependovirus; Adeno-Associated Viruses; Dependoparvovirus; adeno associated virus group; 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; Analgesics; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; pain killer; pain medication; pain reliever; painkiller; inhibitor/antagonist; inhibitor; Clinical Trials; Down-Regulation; Downregulation; Drug abuse; abuse of drugs; abuses drugs; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Exhibits; Family; 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; Genome; Human Genome; human whole genome; Goals; Human; Modern Man; Hypersensitivity; Allergy; Ion Channel; Ionic Channels; Membrane Channels; Lead; Pb element; heavy metal Pb; heavy metal lead; Mus; Mice; Mice Mammals; Murine; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Numbness; Loss of Sensation; Pain; Painful; Patients; Proteins; Quality of life; QOL; Reagent; Repression; Risk; Safety; Sodium Channel; Sodium Ion Channels; Specificity; Testing; Zinc Fingers; Zinc Finger Domain; Zinc Finger Motifs; Guide RNA; gRNA; chronic pain; Polyneuropathy; base; dosage; Organ; improved; premature; prematurity; Phase; Variant; Variation; Evaluation; Nociception; nociceptive; nonhuman primate; non-human primate; Opioid; Opiates; Therapeutic; Genetic; tool; Severities; Treatment Period; treatment days; treatment duration; Sensory; System; cancer pain; experience; voltage; Toxicities; Toxic effect; novel; Human Cell Line; Regulation; response; Adverse effects; Intervention Strategies; interventional strategy; Intervention; small molecule; Address; Dose; Motor; Cancer Patient; Epigenetic Process; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; transmission process; Transmission; safety study; epigenomics; design; designing; novel strategies; new approaches; novel approaches; novel strategy; Persistent pain; constant pain; lasting pain; on-going pain; ongoing pain; Population; innovation; innovate; innovative; mouse genome; 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; induced pluripotent stem cell; iPS; iPSC; iPSCs; addiction; addictive disorder; alternative treatment; Pain intensity; transcriptome sequencing; RNA Seq; RNA sequencing; RNAseq; epigenome; precision medicine; precision-based medicine; Chemotherapy-induced peripheral neuropathy; 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; clinical development; pain reduction; reduce pain; chronic pain patient; patient with chronic pain; pain relief; relieve pain; side effect; animal safety; efficacious treatment; efficacious therapy