The Peripheral Nerve Society (PNS) hosted its 2024 Annual Meeting from June 22 - 25, 2024 at the Palais des Congrès de Montréal in Montréal, Canada. This premier event brought together scientists, physicians, and healthcare professionals to discuss advancements in peripheral neuropathy research. The meeting featured educational courses, mini symposia, special interest group sessions, and networking opportunities, fostering collaboration and innovation in the field.
NerveSim® is a 3D human peripheral nerve model comprised of iPSC sensory neurons and human primary Schwann cells for screening potential neuropathic treatments. In this study, we targeted SARM1, a mediator of neurodegeneration, to ameliorate vincristine-induced peripheral neuropathy. SARM1 is a positive regulator of neuronal cell death and plays a key role in Wallerian degeneration following axonal injury. Its intrinsic NADase activity is normally autoinhibited but is activated in response to neuronal injury leading to axonal NAD+ depletion, metabolic disfunction, and cell death.
We selected three compounds from literature to assess the efficacy of SARM1 inhibition in protecting NerveSim® from vincristine induced electrophysiological dysfunction and morphological degeneration. DSRM-3716 and NB-7 inhibit SARM1’s NADase activity through adduct formation during NAD+ hydrolysis while WX-02-37 prevents the formation of active SARM1 through covalent modification that locks it in the autoinhibited state. Daily electrophysiological recordings were performed for the first 3 days of dosing with images taken Monday/Wednesday/Friday.
All three inhibitors demonstrated protection by delaying electrophysiological dysfunction of our 3D human peripheral nerve model. Vincristine exposure without SARM1 inhibition exhibited a time-to-50% electrophysiological activity of 1.1 days. This time was increased to 1.4, 1.6, and 1.5 days for DSRM-3716 (6 uM), NB-7 (0.6 uM) and WX-02-37 (0.24 uM), respectively.
Morphological protection was assessed through quantification of fiber length from brightfield images and showed more pronounced structural preservation than electrophysiological protection. Notably, after 7 days of dosing, NB-7 (3 uM) and WX-02-37 (0.24 uM) demonstrated significant morphological protection that resembled controls not exposed to vincristine.
Limitations of this study include the use of a high, sustained dose of vincristine that deviates from in vivo plasma concentration curves. This disparity may explain the relatively modest observed functional protection. In conclusion, human NerveSim® is a novel pre-clinical peripheral nerve model well suited for evaluating neuroprotection.
