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Neurons from Stem Cells Produced for Overdose Therapy Tests

Two ambulances at hight

(Patrick Mannion, Flickr.

8 Sept. 2023. Researchers use stem cells to generate human neurons resembling those in the brain that control breathing during opioid reactions, for eventual chip devices to test overdose therapies. A team from University of Central Florida and the organ chip-model developer Hesperos Inc. describe their findings in yesterday’s issue of the journal Advanced Biology.

According to Centers for Disease Control and Prevention, the U.S. is now in a third wave of opioid overdose deaths, driven almost entirely by synthetic opioids such as fentanyl. CDC says the number of drug overdose deaths jumped more than 16 percent from 2020 to 2021, the last full year of data, with three-quarters of the 107,000 overdose deaths from opioids. When overdoses occur, breathing quickly becomes slower and shallower, a condition called opioid-induced respiratory depression and a major cause of overdose death.

Researchers led by James Hickman, professor of chemistry at University of Central Florida, are seeking more reliable methods than current animal models to test new treatments for opioid overdoses. The key brain region for regulating automatic respiratory rhythm, say the authors, is the preBötzinger Complex, also associated with heart rate and blood pressure. But up to now, preclinical tests of new treatments for opioid overdoses such as naloxone use lab rodents, which have a preBötzinger Complex region in their brains, but does not function the some way as humans. Thus, say the authors, a preclinical testing process is needed with human preBötzinger Complex neurons to provide better assessments of safety and efficacy.

Linked to simulate multiple organ functions

Hickman is also co-founder and chief scientist at Hesperos Inc. in Orlando, Florida that develops models of human organs on small chip devices for testing new drugs for toxicity, safety, and efficacy. The company’s technology recreates functions of organs, with fine channels and wells engraved into clear plastic, lined with human cells and tissue, and connected electronically for measurement and control. Hesperos says its organ models can also be linked together to simulate multiple organs. The company says its devices include brain models.

In the paper, Hickman and colleagues including Hesperos staff created a model for testing opioid overdose treatments with neurons like those found in the human preBötzinger Complex. The authors say they produced the neurons by transforming induced pluripotent stem cells, so-called adult stem cells, which they confirmed by testing for characteristic biomarker proteins and electrophysiological responses. The researchers then tested the generated neurons with escalating doses of four natural and synthetic opioid compounds: codeine, methadone, fentanyl, and the opioid peptide DAMGO. The results show characteristic reactions to the four opioids by inhibiting the firing of the generated neurons. A subsequent test also shows characteristic reactions to the presence of naloxone by recovering activity in the neurons earlier exposed to opioids.

Generating neurons similar to those in the human preBötzinger Complex, say the authors, is the first step in creating a chip device emulating opioid overdose. Hesperos says the next stages will integrate a brain chip with the generated neurons into a multi-organ model that includes liver, heart, kidney, and skeletal muscle to simulate reactions to opioid overdoses in other parts of the body. Hickman says in a Hesperos statement that the researchers’ work “will provide invaluable insights into understanding opioid addiction and recovery, paving the way for more effective treatments and ultimately saving lives.”

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