Abstract
Background & Purpose
Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of drugs like vincristine, causing distal axonal degeneration through Wallerian-like mechanisms. SARM1, a key protein in axonal degeneration, has emerged as a potential target for neuroprotection. However, effective human-relevant in vitro models are needed to evaluate SARM1 inhibition strategies. 28bio developed NerveSim®, a 3D nerve-on-a-chip platform, to assess neurotoxicity and neuroprotection in sensory peripheral nerves. This study investigates the impact of SARM1 inhibitors (DSRM-3716, NB-7, WX-02-37) on vincristine-induced neurotoxicity using electrophysiological and morphological growth metrics.
Methods
- NerveSim® Model Development:
- Human iPSC-derived sensory neurons and primary Schwann cells were co-cultured in a 24-well embedded electrode array (EEA) plate for high-throughput functional testing.
- Cultures were grown for 43 days to allow for axon bundle formation.
- Electrophysiology-Based Neurotoxicity Screening:
- Vincristine was applied at five concentrations over seven days.
- Compound action potential (CAP) analysis assessed nerve conduction velocity (NCV) and signal integrity.
- SARM1 Inhibitor Testing:
- DSRM-3716, NB-7, and WX-02-37 were co-administered with 30 nM vincristine.
- Functional and morphological assays measured electrophysiological protection and axonal integrity.
Results
- Vincristine-Induced Neurotoxicity:
- Significant CAP amplitude and velocity loss was observed within 16 hours at high doses.
- IC50 shifted from ~30 nM to ~1 nM over a week, showing cumulative neurotoxic effects.
- SARM1 Inhibitor Effects:
- NB-7 and WX-02-37 showed partial functional neuroprotection, delaying neurotoxicity in the early treatment period.
- Morphological growth analysis confirmed NB-7 and WX-02-37 significantly preserved axonal structure, while DSRM-3716 showed minimal protection.
- Key Findings:
- NB-7 and WX-02-37 provided dose-dependent morphological neuroprotection, but functional protection diminished over time.
- High doses of WX-02-37 caused toxicity, aligning with literature reports.
Conclusion
The NerveSim® platform successfully models vincristine-induced CIPN, providing clinically relevant electrophysiological and morphological metrics. SARM1 inhibition shows potential as a neuroprotective strategy, with NB-7 and WX-02-37 demonstrating promising protective effects. Future studies will optimize SARM1-targeted therapies and expand high-throughput neuroprotection screening using the NerveSim® platform.
