Efficacy and PK/PD Studies

功效和 PK/PD 研究

• 批准号: 10398393
• 负责人: GREGORY O DUSSOR
• 金额: $ 77.32万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398393
• 关键词: Absence of pain sensation; Acute; Acute Pain; Adenosine; Adult; Affect; Afferent Neurons; Amino Acids; Analgesics; Animal Model; Arginine; BCAR1 gene; Base Pairing; Behavioral; Behavioral Model; Capsaicin; Cardiac; Cells; Codon Nucleotides; Coupled; DNA; Development; Diabetes Mellitus; Dideoxy Chain Termination DNA Sequencing; Disease model; Effectiveness; Electrophysiology (science); Enzymes; Exposure to; FDA approved; Female; Gene Deletion; Genetic; Goals; Guanosine; Guide RNA; Harvest; Heart Diseases; Human; IL6 gene; Injections; Inosine; Ions; Lead; Lysine; Malignant - descriptor; Malignant Neoplasms; Mechanics; Mediating; Messenger RNA; Migraine; Modeling; Mus; Muscle; Neurons; Opioid; Organ Donor; Overdose; Pain; Pain Disorder; Patients; Peripheral; Permeability; Pharmaceutical Preparations; Pharmacology; Pilot Projects; Postoperative Pain; Pre-Clinical Model; Prevalence; Property; Protein Isoforms; Protocols documentation; RNA; RNA Editing; Reagent; Recovery; Research Project Grants; Reverse Transcriptase Polymerase Chain Reaction; Shunt Device; Site; Skin; Sodium Channel; Stimulus; Surgical incisions; System; Techniques; Technology; Testing; Therapeutic; Time; Tissue Donors; Transfection; Viral; Withdrawal; addiction; base; behavior test; channel blockers; chronic pain; disability; dsRNA adenosine deaminase; efficacy evaluation; efficacy testing; experimental study; exposed human population; immunogenic; in vivo; male; nerve injury; novel; opioid abuse; pain model; painful neuropathy; patch clamp; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical efficacy; side effect; small molecule; spared nerve; targeted treatment; voltage

Chronic pain is a leading cause of disability, affecting about one-third of adults worldwide, with a prevalence greater than heart disease, cancer, and diabetes combined. Misuse and abuse of opiates have led to a nationwide addiction and overdose crisis. Thus, there is an urgent need for alternative, non-addictive analgesics. Non-selective voltage-gated sodium channel (Nav) blockers are among existing non-addictive FDA-approved drugs which can sometimes provide symptomatic relief for patients. However, their utility is limited by CNS and cardiac side effects. Genetic and functional studies of human pain disorders and animal models of pain have validated NaV1.7, a voltage-gated Na Channel that is preferentially expressed in peripheral neurons, as an attractive target for therapy. Isoform-selective Nav blockers, however, are difficult to generate and those that have been generated are rapidly cleared from the body, limiting their effectiveness. Alternative approaches are needed. We propose a novel, non-addictive approach to treat chronic pain by editing the messages that encode NaV1.7 in order to alter its electrophysiological properties. By changing a single lysine codon to arginine in the ion selectivity filter, the channel will go from being Na+ selective to both Na+ and K+ selective, effectively creating a counter-current shunt that will dampen excitability. Site-Directed RNA Editing (SDRE) refers to novel mechanisms to generate programmed edits within RNAs. It relies on the ADAR (Adenosine Deaminase that Acts on RNA) enzymes, which are endogenously expressed in human cells, including sensory neurons. Directed by a guide RNA (gRNA), SDRE systems convert precisely selected adenosines to inosine, a translational mimic for guanosine, which can recode specific amino acids. For use as an analgesic, editing mRNA is preferable to DNA because it is transient, thus limiting potential off- target effects, including malignant transformations and ADARs are endogenous while enzymes for DNA manipulation (e.g. Cas proteins) are not, thus SDRE will not be as immunogenic. Compared to small molecule channel blockers, SDRE can be more specific, because it relies on Watson-Crick base-pairing of gRNAs for targeting, and its effects are likely longer lasting because they will remain as long as the edited channels are expressed. We propose to use SDRE to edit NaV1.7 K1395R to render the channel permeable to both Na+ and K+. The purpose of RC5 is to test efficacy of 4 candidate sets of human-SDRE reagents promoting NaV1.7 editing using in vivo mouse behavioral pain models of spared-nerve injury (SNI), post-surgical pain, and migraine. RC5 will also test for functional editing of NaV1.7 in sensory neurons taken from mice at the peak time point of behavioral efficacy. As a final bridge to the next development stage, human-SDRE reagents will be tested in cultured human DRG neurons from tissue donors.

慢性疼痛是导致残疾的主要原因之一，影响着全世界约三分之一的成年人，而且发病率很高