Connexin Hemichannel Blockers to Preserve Muscle Function and Improve Recovery After Neuromuscular Trauma

Patients suffering from severe neuromuscular trauma—such as peripheral nerve injury and/or muscular trauma— often experience poor functional recovery largely due to complications of prolonged denervation of the injured muscle target. As such, there is an unmet need for a strategy to prolong the window for surgical intervention following neuromuscular trauma that is capable of attenuating muscle atrophy and improving muscle reinnervation, thereby increasing the likelihood for meaningful functional recovery. Our multi-disciplinary research team is pioneering the use of boldine, an orally active small molecule known to block connexin (Cx) hemichannels (HC), as the first pharmacological treatment to prevent the detrimental effects associated with prolonged denervation following severe nervous system and/or neuromuscular injuries. The purpose of the current project is to complete preclinical mechanistic and efficacy studies in rodent and porcine models of neuromuscular trauma in order to accelerate the translation of this promising therapy. This project will initially gain a mechanistic understanding of the benefits of blocking Cx HC function following neuromuscular trauma based on comprehensive molecular, genomic, and physiological measurements (Aim 1). We will also evaluate the ability of this strategy to attenuate muscle atrophy, enhance muscle reinnervation, and improve functional recovery using established rodent (Aim 2) and porcine (Aim 3) preclinical models. Here, we will establish the dose and timing of boldine administration in conjunction with the optimal window for neurosurgical repair. This will enable the evaluation of boldine efficacy in mitigating the effects of prolonged muscle denervation and supporting muscle reinnervation and functional recover following delayed repair in a rat model of nerve injury. Next, we will validate effective boldine dosing in pigs and characterize the effects of boldine in preserving muscle structure and function in a prolonged denervation model. Finally, we will demonstrate the efficacy of boldine on muscle reinnervation and functionality following delayed nerve repair in pigs. The current proposal will accelerate our efforts for translation by demonstrating efficacy in both small and large animal models of nerve injury and the acquired data will be used in partial support of future regulatory filings. These efforts will significantly de-risk the translation of this technology and will provide a framework for future testing of clinical-grade drugs suitable for pivotal safety studies. Overall, this approach may mitigate the significant detrimental consequences of prolonged denervation and enable greater functional recovery in Veterans afflicted with currently intractable trauma-related deficits, thereby greatly improving their mobility, independence, and quality of life.