Remodeling of Sensory Neurons for Acute Pain Management
A pressing demand exists for innovative approaches to manage acute human pain while mitigating the risk of Substance Use Disorders (SUDs). Traditional pain medications, such as narcotics and anesthetics, while effective, lack neuron-specific targeting and consequently result in undesirable side effects, such as addiction, motor neuron inhibition, and tissue damage. When inflammation occurs, sensory neurons undergo actin polymerization, leading to heightened sensitivity of purinergic receptors and the manifestation of abnormal pain responses. The potential solution lies in targeted actin remodeling, yet the challenge lies in the absence of small-molecule inhibitors that possess the required specificity for sensory neurons to correctly modulate the cytoskeleton.
Neurocarrus introduces an innovative therapeutic strategy for nociceptive pain, revolving around a newly engineered protein known as N-001. This groundbreaking biologic drug selectively targets sensory neurons and operates exclusively at the intra-cellular level, inducing limited and reversible depolymerization of the axon-associated actin cytoskeleton. N-001 offers the advantage of specificity for sensory neurons while harnessing the peripheral nervous system’s characteristics to locally alleviate pain without interfering with the central nervous system.
Neurocarrus has successfully completed an SBIR Phase I study, affirming the viability of N-001 as a pain management solution. The results demonstrate that N-001 effectively managed nociceptive post-operative pain, outperforming bupivacaine by reducing mechanical allodynia and gait dysfunction in a mouse paw incision model while sustaining its efficacy for an impressive three days compared to bupivacaine’s mere six hours. Furthermore, N-001 exhibited extended post-operative pain management benefits in a nerve block model relative to bupivacaine. The mechanism of action was validated in vivo, highlighting its co-localization with CGRP-positive sensory neurons, not motor neurons, and quantifiable monitoring through ADP-ribosylated actin as an indicator of F to G actin neuronal content. Preliminary assessments of ADME, toxicology, and immunogenicity revealed no adverse effects on organ function, furnished critical pharmacokinetic data, and detected non-neutralizing antidrug antibodies only after multiple doses. These findings establish specific benchmarks for the application of N-001 as a post-operative pain therapeutic, thereby strengthening its potential for use in clinical pain management.
In this SBIR Phase II initiative, Neurocarrus will fine-tune the production and formulation of N-001, along with the establishment of manufacturing standards and controls to create Good Laboratory Practice (GLP)-grade N-001. GLP-grade N-001 will be employed in pivotal pre-clinical investigations to demonstrate its in vivo safety using two preclinical animal models, C57BL/6 mice, and Beagle dogs. Additionally, GLP-grade N-001 will be utilized for efficacy assessments as a pain treatment after peripheral joint surgery, employing a mouse distal tibial limb fracture model. The successful completion of this project will pave the way for an investigational new drug filing (IND), facilitating future clinical trials.