Preserving The Neuromuscular Junction After Denervation: Therapeutic Potential Of The MuSK Agonist ARGx-119

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PURPOSE: After an injury to a peripheral motor nerve, denervated muscles undergo degeneration of specialized postsynaptic motor endplates (MEPs) at the neuromuscular junction (NMJ). Although axonal regeneration is possible, the slow rate of axonal growth often prevents reinnervation before MEPs are lost, limiting functional recovery. Because loss of MEPs narrows the therapeutic window for surgical nerve repair or transfer, strategies that preserve or restore NMJ structure are critical to improving long-term outcomes for patients with traumatic nerve injuries. Previous clinical studies have reported functional improvement following nerve transfer beyond the conventional 6-month post injury treatment window in patients who still retain viable MEPs. ARGx-119, a muscle-specific kinase (MuSK) agonistic antibody, has been shown to rescue structural and functional deficits of the NMJ in congenital Myasthenia gravis. We hypothesized that ARGx-119 can reduce MEP degeneration and preserve receptor clustering following denervation, and, in muscles where MEPs have fully degraded, may induce reformation of MEPs. METHODS: A murine model of traumatic sciatic nerve injury was established via transection. Animals were divided into two experimental groups. In group 1, the preservation study, mice received intraperitoneal injections of 20 mg/kg ARGx-119 or saline (control) every two weeks after nerve transection and were euthanized at 1, 2, 3, or 4 months. Tibial muscles were harvested to assess the ability of ARGx-119 to reduce MEP degeneration. In group 2, a reformation/resurrection study, mice did not receive intraperitoneal injections until four months after transection, when their denervated MEPs had fully degraded. They then received intraperitoneal injections of 20 mg/kg ARGx-119 or saline every two weeks and were euthanized after 2, 4, or 6 weeks of treatment. Tibial muscles were collected to determine whether ARGx-119 could induce acetylcholine receptor clustering and reformation of MEPs. All samples were stained with alpha bungarotoxin, synaptophysin, and neurofilament and imaged in 3D using the Keyence BZ-X810 to evaluate MEP morphology. RESULTS: In the preservation study, ARGx-119 delayed MEP degradation and preserved acetylcholine receptor clustering following nerve transection when compared against controls, which showed complete loss of MEPs. The preserved structures exhibited both plaque-like morphology and scattered receptor distribution. In the reformation/resurrection study, ARGx-119 induced new clusters of acetylcholine receptors at all treatment timepoints (2, 4, and 6 weeks), whereas no MEPs were observed in controls. However, these regenerated MEPs did not exhibit the typical pretzel-like morphology of native MEPs and instead showed scattered receptor distribution within the endplate region. CONCLUSION: These preliminary results suggest that ARGx-119 can both preserve existing NMJs and induce post-synaptic receptor clustering in previously denervated muscle. Ongoing studies incorporating blinded dosing, extended timepoints, and functional assessment after surgical repair are needed to further characterize dose-response effects and functional outcomes. This work provides support that ARGx-119 holds potential to improve functional recovery following surgical reconstruction of traumatic nerve injuries by extending the window of MEP preservation at the NMJ. *Source: https://ps-rc.org/meeting/Program/2026/41.cgi*

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