SBIR-STTR Award

There is an urgent need for new approaches to treat acute human pain without the risk of Substance Use Disorders (SUDs). The most effective approved pain pharmaceuticals, including narcotics and anesthetics, are not neuron-specific and consequently suffer from off-target effects like addiction, inhibition of motor neurons, and destruction of the surrounding tissues. When inflammation occurs, actin polymerization occurs in sensory neurons, leading to the sensitization of purinergic receptors and abnormal pain behaviors. Targeted actin remodeling could be an effective approach to reduce acute nociceptive pain, but there are no small-molecule inhibitors with adequate specificity for sensory neurons that correctly modulate the cytoskeleton. Neurocarrus proposes a new therapeutic approach for nociceptive pain based on an innovative engineered protein called N-001 that selectively targets sensory neurons and acts only at an intra-cellular level inducing limited and reversible depolymerization of the axon-associated actin cytoskeleton. This innovative biologic drug will provide specificity towards sensory neurons while leveraging the features of the peripheral nervous system to eliminate pain locally without interacting with the central nervous system. In vivo, N-001 administration by subcutaneous injection prevents acute pain in rodent models at lower doses and with a longer duration than standard opiates. Further advancement of N-001 as a therapeutic candidate for nociceptive pain requires demonstration of the feasibility of using N-001 as a product for human pain management. In this Phase I SBIR project, Neurocarrus will evaluate the response of mice to post-operative pain after treatment with N-001. The selective neuron targeting ability of N-001 will be validated by generating in vivo histologic data supporting its mechanism of action. The identification of nociceptor subtypes that are sensitive to actin depolymerization and the ability to selectively silence them would establish specific metrics for the use of N-001 as a pain therapeutic. Finally, a demonstration of acceptable drug pharmacology will be performed to de-risk future IND-enabling studies in Phase II.

Public Health Relevance Statement:
PROJECT NARRATIVE Neurocarrus is developing an innovative engineered protein that can specifically target sensory neurons to replace small molecule therapeutics that are used for acute pain treatment. This biologic drug can leverage unique features of the peripheral nervous system to eliminate pain signals locally without interacting with the central nervous system, thereby avoiding risks of addiction. Neurocarrus will offer a tenable solution to the growing opioid epidemic and public health problem of acute nociceptive pain management.

Project Terms:
absorption; Actins; Acute; Acute Pain; Acute pain management; addiction; Affect; afferent nerve; Afferent Neurons; Aftercare; American; Analgesics; Anesthetics; Animal Behavior; Axon; base; behavior change; Behavioral; Binding; Biological; burden of illness; Chemicals; Clinical; Clinical Trials; Cytoskeleton; Data; depolymerization; Dizziness; Dose; drug action; drug distribution; Drug Formulations; Drug usage; effective therapy; efficacy study; Engineering; Enzyme-Linked Immunosorbent Assay; Esthesia; Evaluation Research; Excretory function; experience; FDA approved; fight against; Foundations; Fracture; Future; Gait; Health; Histocytochemistry; Histologic; Human; Immunology; improved; In Vitro; in vivo; Individual; Inflammation; inhibitor/antagonist; innovation; Label; Light; mechanical allodynia; Mechanics; meetings; Metabolism; Microscopy; Modification; Motor; Motor Neurons; mouse model; Mus; Narcotics; Nausea; Nerve; Nerve Fibers; Neuraxis; Neurons; Nociception; Nociceptors; novel strategies; novel therapeutic intervention; Operative Surgical Procedures; Opioid; opioid epidemic; Pain; pain behavior; Pain management; pain model; pain relief; pain signal; Peripheral; Peripheral Nervous System; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Physiology; polymerization; Polymers; Postoperative Pain; pre-clinical; Preclinical Drug Development; prevent; Protein Biochemistry; Protein Engineering; Proteins; Public Health; Purinoceptor; Quality of life; Research Personnel; response; Risk; Rodent Model; side effect; Site; Small Business Innovation Research Grant; small molecule; small molecule inhibitor; small molecule therapeutics; Specificity; standard of care; Stimulus; Subcutaneous Injections; Substance Use Disorder; Surgical incisions; Technology; Therapeutic; therapeutic candidate; Therapeutic Uses; Thermal Hyperalgesias; tibia; tissue injury; Tissues; Touch sensation; Toxicology

There is an urgent need for new approaches to treat acute human pain without the risk of Substance UseDisorders (SUDs). The most effective approved pain pharmaceuticals, including narcotics and anesthetics, arenot neuron-specific and consequently suffer from off-target effects like addiction, inhibition of motor neurons, anddestruction of the surrounding tissues. When inflammation occurs, actin polymerization occurs in sensoryneurons, leading to the sensitization of purinergic receptors and abnormal pain behaviors. Targeted actinremodeling could be an effective approach to reduce acute nociceptive pain, but there are no small-moleculeinhibitors with adequate specificity for sensory neurons that correctly modulate the cytoskeleton. Neurocarrusproposes a new therapeutic approach for nociceptive pain based on an innovative engineered protein called N-001 that selectively targets sensory neurons and acts only at the intra-cellular level inducing limited andreversible depolymerization of the axon-associated actin cytoskeleton. This innovative biologic drug will providespecificity towards sensory neurons while leveraging the features of the peripheral nervous system to eliminatepain locally without interacting with the central nervous system.Neurocarrus has completed an SBIR Phase I that has proven the feasibility of N-001 as a pain managementtherapy. Results show that N-001 managed nociceptive post operative pain by efficiently reducing mechanicalallodynia and gait dysfunction in a mouse paw incision model relative to bupivacaine but with a significantlylonger duration of activity. N-001 retained efficacy for 3 days relative to only 6 hours for bupivacaine. N-001 wasalso assessed as an anesthetic agent in a nerve block model where it also showed a significantly increasedduration of post operative pain management relative to bupivacaine. N-001's mechanism of action was validatedin vivo, showing that it co-localizes with CGRP positive sensory neurons not motor neurons, and can bequantitatively monitored using ADP-ribosylated actin as a measure of F to G actin neuronal content. PreliminaryADME, toxicology and immunogenicity assays showed no adverse effects on organ function, providedpharmacokinetic information, and non-neutralizing antidrug antibody formation only after multiple doses. Thesedata establish specific metrics for the use of N-001 as a post operative pain therapeutic thereby strengtheningthe potential for use of N-001 in clinical pain management.In this SBIR Phase II project, Neurocarrus will optimize the production and formulation of N-001 as well as thedevelopment of manufacturing standards and controls for obtaining GLP-grade (Good Laboratory Practice) N-001. GLP-grade N-001 will be used to perform pivotal pre-clinical studies to demonstrate its in vivo safety usingtwo preclinical animal models (C57BL/6 mice and Beagle dogs). GLP drug will also be used for efficacy studiesas a treatment for pain after peripheral joint surgery using a mouse distal tibial limb fracture model. Thecompletion of this project will support an investigational new drug filling (IND) enabling future clinical trials.

Public Health Relevance Statement:
PROJECT NARRATIVE Neurocarrus is developing an innovative engineered protein, which can specifically target sensory neurons, to replace small molecule therapeutics that are used for acute pain treatment. This biologic drug can leverage unique features of the peripheral nervous system to eliminate pain signals locally without interacting with the central nervous system, thereby avoiding risks of addiction. Neurocarrus will offer a tenable solution to the growing opioid epidemic and public health problem of acute nociceptive postoperative pain management.

Project Terms:
<21+ years old>