A human iPSC-derived sensory neuron platform for high-throughput discovery of neuroprotectants against chemotherapy-induced peripheral neuropathy

ABSTRACT: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect of cancer treatment, yet the lack of predictive human models has hindered therapeutic progress. We have established a scalable model of paclitaxel-induced axon degeneration and neurotoxicity in iPSC-derived sensory neurons, suitable for high-throughput discovery of neuroprotective compounds. Using this platform, we screened 192 kinase inhibitors and identified 19 hits that commonly inhibited three STE20 kinases - MAP4K4, MINK1, and TNIK. Genetic knockdown revealed that multi-kinase inhibition of STE20 kinases is required for neuroprotection against paclitaxel. Moreover, selective pharmacological inhibition of STE20 kinases rescued paclitaxel-induced axon degeneration in iPSC-derived sensory neurons and primary human DRG, as well as preserved intraepidermal nerve fiber density in a mouse model of CIPN. These results establish a translational human sensory neuron platform for target and drug discovery in CIPN.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Sensory Processing Neuron

DISEASE(S): Sensory Peripheral Neuropathy

SUBMITTER: Marian Kalocsay  

LAB HEAD: Clifford Woolf

PROVIDER: PXD074954 | Pride | 2026-04-03

REPOSITORIES: Pride