Investigators at The University of Texas at Dallas and Anatomic Engage in Collaboration to Discover Non-addictive Analgesics
Key to the collaboration will be the use of Anatomic’s RealDRG™ nociceptors as a tool for drug discovery.
MINNEAPOLIS, MN — Nov 8th, 2021 — Pain is a major medical problem that affects a huge portion of the population. Existing therapeutics for pain are often ineffective, leaving many with few options to alleviate their pain. Despite decades of research and substantial investment, few treatments have emerged that can ameliorate pain without harmful side effects such as addiction. New model systems that could be used to develop more effective pain therapeutics would greatly benefit the scientific field and the patients who suffer from pain.
Investigators at the Center for Advanced Pain Studies (CAPS; paincenter.utdallas.edu) at the University of Texas at Dallas are focused on developing new, non-addicting pain medicines. As part of these efforts, CAPS Investigators Drs. Benedict Kolber, Theodore Price and Gregory Dussor have been striving to develop better model systems that more accurately reflect human pain-sensing neurons, called nocicpetors. Says lead investigator Dr. Kolber, “You can create unlimited amounts of a cell type expressing a single human pain-related channel, but it will be missing the bigger picture on what pain is all about. On the other hand, you can use the actual human nociceptors from cadavers that are the real deal, but they’re nearly impossible to obtain. It’s been difficult to find cells that reflect human nociceptor biology well enough that are available in quantities useful for drug development programs. It’s really been holding investigators back.”
As the field has struggled with this fundamental problem, investigators at the start-up Anatomic were brewing up a solution. Anatomic has learned to manufacture human nociceptors very rapidly, reproducibly, and at scale from human pluripotent stem cells (hPSCs). By mimicking natural processes that occur during human gestation, Anatomic ushers hPSCs — which can transform into any cell type in the human body — into nociceptors exclusively. This manufacturing prowess, however, means nothing if the end product doesn’t function as expected. “As you develop and look to apply these very complex technologies that are supposed to reflect actual human biology, people are always going to ask how close you are to the real thing. We became familiar with the work of the folks at UT Dallas such as Drs. Price and Dussor who are looking to create a benchmark for these pain-sensing neurons, and we asked them how ours might compare,” says Anatomic CEO Patrick Walsh.
Drs. Price and Dussor’s group has been working for years to molecularly characterize human nociceptors. While substantial knowledge has been gained on rodent sensory neuron biology, human sensory nociceptors are different in many important ways. “The receptor composition of human nociceptors varies quite substantially from rodents, suggesting that therapeutics targeting these cells need to be developed starting with human cells,” said Dr. Price. “It very much explains why we have seen so much clinical failure for novel analgesics: The systems we have been using to identify targets just do not have a one-to-one parallel in human cells. The knowledge gained is invaluable, but the targeting needs the precision we can gain by starting with the human cells.”
The opportunity for breakthroughs in the pain field has never been better. Great advances in fundamental understanding of nociceptors across species have been made in the past two decades and support from NIH has been accelerating, in large part due to the Helping to End Addiction Long Term (HEAL) Initiative. Says Dussor, “We’ve been looking for upgraded tools for quite some time. The hiPSC-derived nociceptors from Anatomic are very impressive and meet many of the benchmarks we look for in a model system for drug screens. When the people at Anatomic reached out claiming to have new technology, of course we were a bit skeptical, but after having seen the data and worked with the cells, they might have the next best thing to actual human tissue. What these guys have done is very unique.”
Part of what makes the cells unique is their response to natural compounds such as capsaicin, the “spice chemical” found in chili peppers. There have been very few reports of hiPSC-derived sensory neurons with large capsaicin responses. “Most human nociceptors in the DRG respond to capsaicin, so this is almost the first question anyone asks when a group claims to have a good model. It’s a very difficult argument to win if you’re claiming to have a good model for human pain without a robust capsaicin-responsive sensory neuron population. We are confident that we have that key response profile,” remarked Vince Troung, COO of Anatomic.
Leveraging the ability of Anatomic’s RealDRG to respond to natural compounds like capsaicin, and inflammatory mediators like cytokines, the collaboration focuses on identifying additional naturally derived compounds that can be repurposed for use as pain therapeutics. Says Dr. Kolber, “Organisms over billions of years have co-evolved systems that both sense and create sensory modulators, whether they be irritants or analgesics. Either type of chemical when discovered can be re-engineered to provide pain relief. The natural world is a treasure trove of possible analgesics. You need first a way to detect them — which we believe we now have — and after that only the ambition to seek them out.”
About
The Kolber lab is focused on understanding the complex biology in both the peripheral and central nervous systems that contribute to the development and treatment of chronic pain. The lab utilizes interdisciplinary approaches including behavior, physiology, and genetics to understand pathology and find new drugs to treat pain. Drug discovery efforts are focused on utilizing both novel and classic natural product sources.
The Price/Dussor lab is focused on understanding the underlying biology of nociceptors across species, with a growing emphasis on human nociceptors. The lab strives to identify key molecular targets for pain and migraine treatment and then develop drugs that can move toward clinical development. Five companies have been spun out of the Price/Dussor lab at UT Dallas, most recently Doloromics, which is part of the Illumina Accelerator program.
Anatomic provides model systems for human pain useful for the development of novel analgesics. Anatomic’s breakthrough manufacturing platform enables the scalable and consistent production of human pluripotent stem cell derived sensory neurons, or RealDRG, useful for characterization of the molecular mechanics of pain in low, medium, and high throughput screening settings. More Info: www.anatomic.tech. Email: info@anatomic.tech.
https://www.bio.org/sites/default/files/BIO_HPCP_Series-Pain_Addiction_2018-02-08.pdf