Development of oral KCC2 enhancer drug for treatment of painful diabetic neuropathy. : There is a need for more effective drug treatments for diabetic neuropathic pain (DNP), which affects one-third of people with diabetes. Current analgesics have unpredictable efficacy and debilitating side effects that can outweigh pain relief. Despite its impact on quality of life, there are no disease-modifying treatments for DNP. In recent years, growing evidence shows that neuropathic pain in diabetic neuropathy and other disorders is caused by spinal disinhibition secondary to hypofunction of KCC2, a CNS-specific chloride transporter that is essential for neuronal responses to inhibitory neurotransmission. KCC2-enhancing treatments are effective in animal models of neuropathic pain, including diabetic rats, with analgesic effects in both males and females. Therefore, treatments that restore KCC2 function and neuronal chloride homeostasis within dorsal spinal cord could directly address central pathological mechanisms of DNP, therapy alleviating neuropathic pain and improving quality of life of DNP patients. AXONIS Therapeutics is advancing a first-in- class oral KCC2 enhancer drug, AXN-006-01-3, towards clinic with GLP-toxicology studies planned for Q4 2022. In this Phase 1 SBIR application, we aim to complete key proof of concept studies to show that AXN- 006-01-3 can treat neuropathic pain in a DNP model. Additionally, impaired HRDD is a biomarker of spinal disinhibition, and correlates with drug analgesic efficacy, in both DNP models and patients. Because HRDD impairments reflect KCC2 hypofunction and respond to KCC2 treatments, we will examine HRDD as a translational, electrophysiological biomarker of our KCC2-enhancing small molecule drug for DNP. Finally, we will investigate PK/PD relationships using a confocal-based neuronal KCC2 biomarker.
Public Health Relevance Statement: Project narrative: One-third of diabetic patients will suffer from painful diabetic neuropathy, and current treatments have unpredictable efficacy and debilitating side effects that can outweigh pain relief. Hypersensitivity to pain in diabetic neuropathy involves the disinhibition of pain signals within the spinal cord. We are developing an orally administered drug that acts to rebalance the neuron activity within the spinal cord, without sedative side effects, in order to alleviate neuropathic pain and improve quality of life of DNP patients.
Project Terms: Oral Drug Administration; intraoral drug delivery; Oral Administration; Affect; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; pain killer; pain medication; pain reliever; painkiller; Analgesics; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Blood - brain barrier anatomy; Blood-Brain Barrier; Hemato-Encephalic Barrier; bloodbrain barrier; Chlorides; Mental Depression; depression; Diabetes Mellitus; diabetes; Diabetic Neuropathies; diabetes-associated neuropathy; Disease; Disorder; Down-Regulation; Pharmacotherapy; Drug Therapy; drug treatment; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Electrophysiology (science); Electrophysiology; Neurophysiology / Electrophysiology; electrophysiological; Equilibrium; balance; balance function; Female; Future; gene therapy; DNA Therapy; Gene Transfer Clinical; Genetic Intervention; gene repair therapy; gene-based therapy; genetic therapy; genomic therapy; Goals; H-Reflex; Homeostasis; Autoregulation; Physiological Homeostasis; Hyperalgesia; Hyperalgesic Sensations; hyperalgia; Hypersensitivity; Allergy; male; Mus; Mice; Mice Mammals; Murine; Persons; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Pain; Painful; Pathology; Patients; Drug Kinetics; Pharmacokinetics; Potassium; K element; Prodrugs; Drug Precursors; Pro-Drugs; Quality of life; QOL; Rattus; Common Rat Strains; Rat; Rats Mammals; sedative; Spinal Cord; Medulla Spinalis; Spinal cord injury; Spinal Cord Trauma; Spinal Trauma; Spinal cord injured; Traumatic Myelopathy; Vertebral column; Spinal Column; Spine; backbone; Streptozocin; STZ; Streptozotocin; Zanosar; Testing; Time; Toxicology; Translations; translation; Work; Measures; Enhancers; Secondary to; improved; Dorsal; Acute; Chronic; Clinical; Phase; Dorsal Horn of the Spinal Cord; Spinal cord posterior horn; non-painful; nonpainful; not painful; Painless; diabetic; Measurement; Dysfunction; Physiopathology; pathophysiology; Functional disorder; Collaborations; Therapeutic; Diagnostic; Tactile; Oral; Clinic; restoration; allodynia; Spinal; Membrane; membrane structure; drug efficacy; symporter; Co-Transporters; professor; Animal Model; Animal Models and Related Studies; model of animal; pregabalin; 3-isobutyl GABA; neurotransmission; Nerve Impulse Transmission; Nerve Transmission; Neuronal Transmission; axon signaling; axon-glial signaling; axonal signaling; glia signaling; glial signaling; nerve signaling; neural signaling; neuronal signaling; drug metabolism; drug clearance; drug action; Diabetic Neuralgia; Painful Diabetic Neuropathy; Posterior Horn Cells; Dorsal Horn Cells; Dorsal Horn Neurons; Posterior Horn Neurons; Pharmacodynamics; Modeling; Property; response; drug development; small molecule; Address; Dose; global health; Data; in vivo; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Pathologic; Process; Development; developmental; painful neuropathy; neuropathic pain; Disinhibition; intervention efficacy; therapeutic efficacy; therapy efficacy; Treatment Efficacy; Rat model of diabetes; diabetic rat model; diabetic rat; Impairment; treatment effect; standard of care; bio-markers; biologic marker; biomarker; Biological Markers; diabetic patient; mechanical allodynia; mobility enhancement; mobility improvement; optimized mobility; improved mobility; candidate identification; efficacy testing; treatment group; spasticity; pharmacodynamic marker; pharmacodynamic biomarker; clinical candidate; efficacy study; pain model; reduce pain; pain reduction; pain patient; relieve pain; pain relief; pain signal; marker validation; biomarker validation; side effect; PK/PD; pharmacokinetics and pharmacodynamics; in-vivo diagnostics; translational potential; translational opportunities
