R43NS120337

PROJECT SUMMARY 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.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.