Researchers have created patient-specific, in vitro models of an extreme pain disorder using neurons generated from the patients’ stem cells. The researchers used the induced pluripotent stem cell (iPSC)-derived neurons to test an experimental drug, which relieved pain attacks in some patients. The findings highlight how an iPSC disease model could help screen drugs for individual patients, bridging the gap between preclinical and clinical research that has hampered the development of new pain medications. Chronic pain is notoriously difficult to treat, with limited treatment options available.
The sodium channel Nav1.7, which plays a key role in transmitting pain signals in peripheral neurons, has emerged as a major analgesic drug target. Genetic defects disabling the channel are known to cause a pain insensitivity disorder, whereas mutations activing it have been linked to chronic pain, including inherited erythromelalgia (IEM). IEM is a rare condition that causes debilitating pain episodes triggered by mild heat, especially in the hands and feet.
To investigate the potential of a Nav1.7 blocker as a painkiller, Lishuang Cao and colleagues exploited iPSC technology to produce sensory neurons using blood from four IEM patients, who carried different genetic mutations in the sodium channel. These iPSC-derived neurons showed abnormally high excitability and sensitivity to heat, closely resembling features of the disease. Testing the selective Nav1.7 blocker, the researchers found that it reduced the spontaneous firing of these neurons in vitro. In parallel, a single dose of the drug helped curb heat-induced pain attacks in most of the patients. Researchers say that iPSC-based disease models may offer a personalized approach for identifying drugs to treat IEM and other pain disorders.
“Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia,”