TRPA1

A multidisciplinary research group specializing in pediatrics, genetics, and psychophysics has identified wide variation in the sensory perception of a pediatric formulation of ibuprofen -- some that were tied to genetic ancestry, and some that were not. These findings indicate that a range of factors come into play in determining how a medicine tastes to an individual. Although there are some cultural exceptions to the rule, medicines for children are often given in liquid form that is sweetened to make it taste good. But not every child experiences the same medicine in the same way. A multidisciplinary research group specializing in pediatrics, genetics, and psychophysics, co-led by Julie A. Mennella, PhD, Principal Investigator at the Monell Chemical Senses Center, has identified wide variation in the sensory perception of a pediatric formulation of ibuprofen -- some that were tied to genetic ancestry, and some that were not. These findings indicate that a range of factors come into play in determining how a medicine tastes to an individual. Their work, recently published in the International Journal of Molecular Sciences, is the first in a series of studies funded by the National Institutes of Health to look at variation in the taste of medicines. "Taste is personal and determining how individuals differ and why is critical to understanding medication adherence and personal risks," said Mennella. Bitter taste and irritating sensations in the throat are the top reasons for non-compliance, as a child (or adult) is less likely to ingest a medicine that is unpleasant (or tastes bad). However, if a child finds the medicine bottle uncapped and finds it tastes sweet like candy, they may ingest too much. Discovering how individuals differ in sensory perception is especially key when it comes to liquid ibuprofen, which accounts for many unintentional poison exposures among children under the age of six years in the US, according to the U.S. Poison Centers. "Sweetening medicines like ibuprofen is a delicate balance between having it taste good enough that kids take it, but bitter enough that, should they get unguarded access to it, it's irritating enough that they stop drinking it and don't poison themselves" said Mennella. "We found genetic markers, both ancestry-related and independent of it, that could predict if someone would find a medication irritating or pleasantly sweet. If we get to the point of tailor-making medications in the future, knowing these associations could help us design taste specifically for each child in the not-so-distant future." The study included 154 adult panelists from Philadelphia, who represented the diversity of their city. According to a genome-wide association study, 63 had African ancestry, 51 European, 13 South Asian, seven East Asian, and seven American. They underwent training in sensory methods and then rated the sweetness, irritation, bitterness, and palatability of a pediatric formulation of a berry-flavored ibuprofen after swallowing, and also after just tasting it without swallowing. Researchers found that panelists of African genetic ancestry had fewer chemesthetic sensations such as tingling or an urge to cough, rated the medicine as tasting sweeter and more palatable than those of European genetic ancestry. Researchers also found a novel association between the TRPA1rs1198875 genetic variation and tingling sensations, independent of ancestry. This is significant as TRPA1 is a family of neuron receptors that are involved in sensory neural response to a variety of chemical irritants found in foodstuff and other medicines. Discovering both an ancestry-related link and non-ancestry-related genetic variation to taste and irritation perception shows that who perceives a medicine as palatable or not is a complicated picture and must consider a variety of factors. This first study was conducted with adults because the sensory measures were complex and included several hour-long test sessions. That does not mean future tests should not include children, Mennella said, adding that this is just the first in a line of studies on the taste of pediatric medicines and methods need to be developed to measure sensory irritation in children. "This is a small study, but it is the first step in showing how research on diverse populations is needed to be able to unravel the genetic, cultural, dietary, and developmental paths that underlie medicine adherence and also risk for poisoning," said Mennella. "It's looking at both sides of the same, very important coin." Findings from this research will affect how sensory tests can be designed in the future. Since participants did both swallow and sip-and-spit tests, the team was able to determine that just tasting medicine allowed predictions and perceptions after swallowing, which could simplify future studies in different age groups. Other studies as part of this National Institutes of Health grant are ongoing, including determining the variation and acceptance of medicines in children. This work was funded by the National Institutes of Health (R01 DC011287). Co-authors are co-first author Mengyuan Kan, University of Pennsylvania (Penn); Joel D. Mainland, Monell Chemical Sense Center; Luis R. Saraiva, Sidra Medicine, Qatar and Monell Chemical Senses Center; Elizabeth D. Lowenthal, Penn (co-PI of grant); Blanca E. Himes, Penn; and M. Yanina Pepino, University of Illinois at Urbana-Champaign.

The pain drug market has many products, but there’s still a need for pills with better properties, such as avoiding addiction. Eli Lilly sees potential in the non-opioid pain drug research from Confo Therapeutics and it’s paying $40 million for rights to the biotech’s most advanced program. The sum is an upfront payment. According to terms of the deal announced Thursday, Indianapolis-based Lilly gets global rights to the Confo drug, CFTX-1554, as well as back-up compounds. As the research progresses, Confo could earn up to $590 million in milestone payments per program, plus royalties if any of these drug candidates reach the market. Belgium-based Confo develops drugs that target G-protein coupled receptors (GPCRs), receptors found throughout the body that are involved in a wide range of physiological functions. While there are many GPCR-targeting drugs on the market, drug hunters have been searching for ways to hit GPCRs thought to be undruggable. Confo, which spun out of Vrije Universiteit Brussel in 2015, says its technology stabilizes GPCRs to address receptors that were previously inaccessible as drug targets. The lead Confo program, CFTX-1554, targets the angiotensin II type 2 receptor (AT2R), a GPCR that has been studied for its role in pain. In particular, this receptor is thought to be a promising target for neuropathic pain, which stems from damage to nerves outside of the brain and spinal cord. Cancer patients can experience neuropathic pain. It’s also associated with diabetic nephropathy and shingles, among other conditions. The Confo drug is small molecule designed to block AT2R. The Phase 1 clinical trial is currently enrolling healthy volunteers and will evaluate multiple doses of CFTX-1554. Lilly won’t pick up development of the program until after Phase 1. The deal gives Confo the option to participate in the funding of future development programs after they show clinical proof of concept. With CFTX-1554, Lilly adds a fourth pain drug to its pipeline. The pharma giant has reached mid-stage clinical development with small molecules that address the targets P2X7, SSTR4, and TRPA1. “CFTX-1554’s progression through the clinic will benefit from Lilly’s experience and global organization, while we will continue to develop and expand our growing, innovative pipeline of GPCR-targeted assets, both small molecules and biologics,” Confo CEO Cedric Ververken said in a prepared statement. Advances in GPCR research have led to several investments and deals in the past year. In early 2022, GPCR startup Septerna launched with $100 million to develop drugs for endocrinology, the central nervous system, metabolic disease, and inflammation. Last fall, AbbVie paid $255 million to acquire DJS Antibodies, a biotech whose technology discovers antibodies that can hit GPCRs. And in January, Structure Therapeutics raised $161 million from its IPO to finance clinical development of its GPCR-targeting drugs for metabolic disorders and cardiopulmonary indications. Photo by Flickr user Jernej Furman via a Creative Commons license

In animal models, social isolation triggers memory and learning deficits that are mediated by hyperactivity of the most abundant brain cell, the astrocyte. Importantly, inhibiting this hyperactivity reversed the cognitive deficits associated with social deprivation. Here is an important reason to stay in touch with friends and family: social isolation causes memory and learning deficits and other behavioral changes. Many brain studies have focused on the effects social deprivation has on neurons, but little is known about the consequences for the most abundant brain cell, the astrocyte. Researchers at Baylor College of Medicine working with animal models report in the journal Neuron that during social isolation, astrocytes become hyperactive, which in turn suppresses brain circuit function and memory formation. Importantly, inhibiting astrocyte hyperactivity reversed the cognitive deficits associated with social deprivation. "One thing we have learned during the COVID pandemic is that social isolation can influence cognitive functions, as previous studies suggested," said co-first author, Yi-Ting Cheng, graduate student in Dr. Benjamin Deneen's lab at Baylor. "This motivated co-first author Dr. Junsung Woo and me to further investigate the effects of social isolation in the brain, specifically in astrocytes." Astrocytes play diverse roles in the brain such as supporting the functions of neurons, participating in synapse formation and function, releasing neurotransmitters and making the blood-brain barrier. "Under normal group housing conditions, astrocytes facilitate and promote circuit function and memory," said Deneen, professor and Dr. Russell J. and Marian K. Blattner Chair of neurosurgery and director of the Center for Cancer Neuroscience at Baylor. He also is the corresponding author of the work. "However, we found that during social deprivation, astrocytes in the brain region known as the hippocampus actually suppress circuit function and memory formation. The broad conclusion is that astrocyte function is tuned to social experiences." Looking for a deeper understanding of the mechanism by which astrocytes of socially-isolated mice cause learning and memory deficits, the researchers studied calcium ions (Ca2+), which previous studies had shown play a central role in astrocyte-mediated learning and memory behaviors. "We evaluated the effect of social deprivation on astrocyte Ca2+ activity and discovered that social isolation greatly increased it, specifically the activity involving Ca2+ channel TRPA1. This in turn was followed by the release of the inhibitory neurotransmitter GABA that put a break on neural circuits involved in memory and learning," Cheng said. "Importantly, both pharmacological and genetic inhibition of TRPA1 reversed the physiological and cognitive deficits associated with social deprivation." "Although social isolation also affects other brain cells, we are very excited about the discovery that specifically manipulating astrocytes is enough to restore learning and memory deficits triggered by social isolation in animal models," Deneen said. "Our findings show a new role for astrocytes in brain physiology," Cheng said. "What astrocytes do is affected by changes in the environment and will reflect in the animal's behavior. In this case, we learned that social interaction is good for astrocytes and therefore, for the brain." Estefania Luna-Figueroa, Ehson Maleki and Akdes Serin Harmanci, all at Baylor College of Medicine, also contributed to this work. This work was supported by U.S. National Institutes of Health (NIH) grants (NS071153, AG071687,NS096096, CA125123 and RR024574), the David and Eula Wintermann Foundation and NIH shared instrument grants S10OD023469, S10OD025240 and P30EY002520. Further support was provided by CPRIT Core Facility Support Award RP180672 and the Eunice Kennedy Shriver National Institute of Child Health & Human Development of NIH under Award Number P50HD103555.