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

Chemotherapy is a crucial treatment for cancer, but it frequently causes severe side effects. One of the most difficult is chemotherapy-induced peripheral neuropathy, a condition that damages the nerves and causes debilitating pain and numbness. Because scientists have lacked good laboratory models of human nerves, finding treatments to prevent this damage has been challenging. To solve this, researchers built a new testing platform using human induced pluripotent stem cells. These are regular adult cells that have been reprogrammed to grow into human sensory nerves. This gave the team a scalable and reliable way to study how paclitaxel, a common chemotherapy drug, causes nerve toxicity and damage.

With this new cellular testing ground, the research team went hunting for protective drugs. They rapidly screened a library of 192 compounds known as kinase inhibitors, which are drugs that block specific proteins involved in cell communication. Out of this batch, they identified 19 compounds that successfully shielded the nerves from chemotherapy damage. By genetically altering the cells, they discovered that protecting the nerves specifically required blocking a combination of three enzymes at the same time: MAP4K4, MINK1, and TNIK.

To confirm their findings, the researchers used targeted drugs to block those three specific enzymes. This approach successfully stopped nerve degeneration in their human cell models. Furthermore, the targeted treatment preserved nerve health and fiber density in a living mouse model experiencing chemotherapy-induced nerve damage.