TRPV1

Researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. University of Michigan researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology. The findings, published in Nature Neuroscience, could help unravel how we sense and suffer from cold temperature in the winter, and why some patients experience cold differently under particular disease conditions. "The field started uncovering these temperature sensors over 20 years ago, with the discovery of a heat-sensing protein called TRPV1," said neuroscientist Shawn Xu, a professor at the U-M Life Sciences Institute and a senior author of the new research. "Various studies have found the proteins that sense hot, warm, even cool temperatures -- but we've been unable to confirm what senses temperatures below about 60 degrees Fahrenheit." In a 2019 study, researchers in Xu's lab discovered the first cold-sensing receptor protein in Caenorhabditis elegans, a species of millimeter-long worms that the lab studies as a model system for understanding sensory responses. Because the gene that encodes the C. elegans protein is evolutionarily conserved across many species, including mice and humans, that finding provided a starting point for verifying the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2). For this latest study, a team of researchers from the Life Sciences Institute and the U-M College of Literature, Science, and the Arts tested their hypothesis in mice that were missing the GluK2 gene, and thus could not produce any GluK2 proteins. Through a series of experiments to test the animals' behavioral reactions to temperature and other mechanical stimuli, the team found that the mice responded normally to hot, warm and cool temperatures, but showed no response to noxious cold. GluK2 is primarily found on neurons in the brain, where it receives chemical signals to facilitate communication between neurons. But it is also expressed in sensory neurons in the peripheral nervous system (outside the brain and spinal cord). "We now know that this protein serves a totally different function in the peripheral nervous system, processing temperature cues instead of chemical signals to sense cold," said Bo Duan, U-M associate professor of molecular, cellular, and developmental biology and co-senior author of the study. While GluK2 is best known for its role in the brain, Xu speculates that this temperature-sensing role may have been one of the protein's original purposes. The GluK2 gene has relatives across the evolutionary tree, going all the way back to single-cell bacteria. "A bacterium has no brain, so why would it evolve a way to receive chemical signals from other neurons? But it would have great need to sense its environment, and perhaps both temperature and chemicals," said Xu, who is also a professor of molecular and integrative physiology at the U-M Medical School. "So I think temperature sensing may be an ancient function, at least for some of these glutamate receptors, that was eventually co-opted as organisms evolved more complex nervous systems." In addition to filling a gap in the temperature-sensing puzzle, Xu believes the new finding could have implications for human health and well-being. Cancer patients receiving chemotherapy, for example, often experience painful reactions to cold. "This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated," Xu said. The research was supported by the National Institutes of Health. All procedures performed in mice were approved by the Institutional Animal Care and Use Committee and performed in accordance with the institutional guidelines. Study authors are: Wei Cai, Wenwen Zhang, Chia Chun Hor, Tong Pan, Mahar Fatima, Bo Duan and X.Z. Shawn Xu of the University of Michigan; and Qin Zheng and Xinzhong Dong of the Johns Hopkins University School of Medicine

Bsense Bio Therapeutics Ltd., a preclinical-stage biopharmaceutical company developing innovative small molecule drug candidates for sensory hyperexcitability disorders, today announced the clinical candidate nomination of their drug candidate, BSEN760, a dual Kv7.2/3 and TRPV1 ion-channel modulator, which heralds a potential breakthrough in the treatment of chronic pain by potentially providing efficacy for a broad spectrum of chronic pain conditions devoid of side effects associated with current standard-of-care (SOC) treatments. BSEN760 is a novel potent and selective, orally active, investigational small molecule drug that simultaneously activates Kv7.2/3 and inhibits TRPV1. The dual mechanism of action (MOA) of BSEN760 underlies the compound’s exquisite potency and synergistic activity in dampening sensory neuron hyperexcitability. Kv7.2/3 and TRPV1 are highly validated therapeutic targets for modulation of sensory hyperexcitability, specifically for pain alleviation; however, significant CNS, renal and thermal side effects have limited successful translation of numerous Kv7.2/3 and TRPV1 drug development programs. The Company’s novel MOA, targeting dual ion-channel modulation, is particularly advantageous compared to current SOC drugs due to its efficacy in models of chronic pain at low (sub-nanomolar) exposures that translate to a wide therapeutic window avoiding side effects. As such, BSEN760 may enter the market with comparable, potentially better, efficacy vs. SOC, and a much improved safety profile. Preclinical studies of BSEN760 demonstrate dose-proportional efficacy in neuropathic and osteoarthritis pain models. Moreover, BSEN760 shows no evidence of motoric impairment/sedation (rotarod) nor effects on core body temperature and thermal sensation, side effects that have precluded clinical development of drugs targeting either Kv7.2/3 or TRPV1. These, and other data, support the Company’s efforts toward full preclinical development of BSEN760 and IND submission by Q1 2025. Haim Belinson PhD., Chief Scientific Officer of Bsense, commented: “The nomination of our dual Kv7.2/3-TRPV1 ion-channel modulator drug candidate, BSEN760, is an exciting step forward for Bsense Bio Therapeutics and the treatment of chronic pain conditions in general. With its unique features of modulating sensory nervous system hyperexcitability by two well validated pain MOAs but without class-related side effects, this asset shows unmatched potential to provide a superior, non-addictive treatment option for chronic pain. We look forward to bringing BSEN760 to the clinic in Q1, 2025 as we work to complete IND-enabling studies.” Alan Brown, Director, AD Brown Medchem Consulting Limited, added: “The exciting pharmacological profile and medicinal chemistry development behind BSEN760 suggest that this compound represents a significant step forward in the development of new pain therapeutics.” Vladimir Skljarevski M.D., Clinical consultant, Principal of VS Biopharma Consulting Inc.: “This novel and unique mechanism of action, involving modulation of two co-located ion-channels, has a potential to provide significant clinical analgesia across a broad range of chronic pain conditions with no addiction/abuse potential.” Sensory hyperexcitability translates to an increase in sensory stimuli, such as proprioception, vision, sound, and touch, as unpleasantly heightened sensations. Pathophysiology could arise from nerve damage, inflammation, and metabolic diseases, all of which may alter the normal function of sensory neurons. Sensory hyperexcitability is observed in a wide variety of neurological disorders, including Epilepsy, Anxiety, Autism, Pain, Tinnitus, and Pruritus to name a few. Sensory hyperexcitability related disorders impact millions of people worldwide. Moreover, these conditions have a profound negative effect on the quality of life of patients and place a significant operational and economic burden on healthcare systems. The multitude of patients suffering from sensory hyperexcitability disorders emphasizes a significant unmet medical need that ranges from a lack of effective pharmacological treatment (i.e., Tinnitus, various Pruritic conditions) to those, in particular chronic pain, with multiple available pharmacological treatments but that demonstrate less-than optimal efficacy often associated with significant side effects as well as, for some, the potential for drug abuse and addiction. In each case, the spatial and mechanistic emergence of sensory hyperexcitability may lead to different and varied clinical manifestations; however, in all cases, the sensory neuronal system’s excessive activity is the hallmark of the disorder. Importantly, the anatomical positioning of dorsal root ganglia (DRG) outside the CNS blood-nerve barrier has made signal transmission and transduction by afferent sensory neurons a prime target for modulating pain signaling to the spinal cord and higher brain centers. As such, modulation of hyperexcitability at the level of DRG neurons where Kv7.2/3 and TRPV1 are predominantly, and mutually, expressed represents a unique, synergistic approach toward providing significant relief coupled with superior tolerability to sensory hyperexcitability disorders. Bsense Bio Therapeutics is developing dual cationic channel small molecule modulators for the treatment of sensory hyperexcitability-related disorders. The goal of the Company’s novel, pioneering approach of targeting multiple neuronal excitability-related mechanisms using a single compound is to achieve greater efficacy and safety compared to current therapeutic approaches that focus on modulation of a single target. Bsense Bio’s approach is based on the targeting of two cation channels, TRPV1 and Kv7.2/3, a ligand-gated and a voltage-gated potassium channel, respectively, which are co-localized on sensory neurons and are widely recognized as prominent players in controlling neuronal excitability. Bsense Bio was established based on the initial discovery and identification by Prof. Bernard Attali and Dr. Asher Peretz from Tel-Aviv University of small molecule compounds demonstrating dual ion-channel activity. Bsense Bio was founded in September 2018 at the FutuRx biotech incubator and is financed by RMGP, OrbiMed Israel Partners, Johnson & Johnson Innovation – JJDC, Takeda Ventures Inc., and the Israeli Innovation Authority (IIA). The content above comes from the network. if any infringement, please contact us to modify.

- Supera-CBD eased heat-related pain due to inflammation quickly and provided long-lasting pain relief lasting up to five hours - Results suggest Supera-CBD may target specific pain pathways, lessening the potential for side effects - MyMD was issued Japanese Patent No. 7293561 B2, covering Supera-CBD as a new molecular entity, in pharmaceutical formulations, and for use in therapeutic treatments BALTIMORE--(BUSINESS WIRE)-- MyMD Pharmaceuticals, Inc.® (Nasdaq: MYMD) (“MyMD” or “the Company”), a clinical stage biopharmaceutical company developing groundbreaking therapies for the treatment of serious and debilitating autoimmune and inflammatory diseases, today announced results from a preclinical study of its investigational cannabinoid Supera-CBD™, a novel, synthetic, non-toxic cannabidiol (CBD) analog. In the study, Supera-CBD targeted and quickly reduced inflammatory pain within 60 minutes, providing pain relief for up to five hours. Comparatively, traditional CBD had no effect on this type of pain in the same study. “These preclinical results illustrate the potential of Supera-CBD to alleviate acute inflammatory pain related to injuries, burns, surgery, and flare-ups from chronic inflammatory conditions such as diabetic neuropathy and shingles,” said Chris Chapman, MD, president, director and chief medical officer, MyMD. “Moreover, these are exciting findings in that the effect demonstrated appears to be targeted, as Supera-CBD alleviated pain due to heat but did not affect pain related to touch in the model of inflammation. This may indicate the potential for fewer side effects compared to traditional opioid pain treatments, without the functional impairment due to numbness in affected areas.” According to study researchers at a major academic center where the study was conducted, the results indicate that Supera-CBD may have an effect on the body’s TRPV1 pain system channels, which control heat-related pain.1 Added Dr. Chapman, “By targeting the TRPV1 channels, which these results indicate Supera-CBD may be capable of, we have the potential to advance treatment in inflammatory-related pain, an area of great patient need.” Dr. Chapman also noted that it was very significant that the “U.S. Department of Justice Drug Enforcement Administration (DEA)’s scientific review concluded Supera-CBD will not be considered a controlled substance or listed chemical under the Controlled Substances Act (CSA) and its governing regulations or require scheduling during development.” Acute pain related to inflammation, burns, and nerve-related pain affects countless individuals worldwide. The global market for pain management was valued at around $36 billion in 2021 and is expected to reach $52 billion by 2026. About Supera-CBD Supera-CBD™ is a synthetic, non-toxic cannabidiol (CBD) analog that is an 8000-times more potent CB2 agonist than plant-based CBD. In addition to its potential role in managing addiction, anxiety, chronic pain and seizures, Supera-CBD has also been shown in preclinical studies to have anti-inflammatory effects. Supera-CBD is a unique synthetic analog of CBD whose structure has been modified to be CB2-receptor selective. Studies to investigate Supera-CBD’s binding and affinity to CB1 and CB2 receptors show that the compound had very low affinity to CB1 and had a four-fold increase in binding to the CB2 receptor in comparison to CBD. Supera-CBD has completed genotoxicity studies, and the company has initiated preclinical pain studies in partnership with Johns Hopkins Medicine. On June 20, 2023, MyMD was issued Japanese Patent No. 7293561 B2, covering Supera-CBD™ as a new molecular entity, in pharmaceutical formulations, and for use in therapeutic treatments. With this latest issuance, the Company now has 23 issued patents worldwide protecting this drug product candidate, along with two pending applications. About MyMD Pharmaceuticals MyMD Pharmaceuticals, Inc. (Nasdaq: MYMD), is a clinical stage biopharma company developing groundbreaking therapies for the treatment of serious and debilitating autoimmune and inflammatory diseases. MyMD’s lead clinical candidate, MYMD-1®, is an orally available next-generation TNF-α inhibitor with the potential to transform the way that TNF-α based diseases are treated. MYMD-1®, with its small molecule design, improved safety pro ability to cross the blood brain barrier, has the promise to provide meaningful therapeutic solutions to patients not served by current TNF-α inhibitors and as a potential therapy for CNS-based inflammatory and autoimmune diseases. The company has completed Phase 2 studies of MYMD-1® for sarcopenia/frailty, a result of the aging process, as well as early-stage trials for rheumatoid arthritis (RA), with the potential to expand into other applications. MyMD’s second therapeutic candidate is Supera-CBD, a novel, synthetic, non-toxic cannabidiol (CBD) analog that is 8000 times more potent a CB2 agonist (activator) than plant-based CBD. In addition to its potential role in managing addiction, anxiety, chronic pain and seizures, Supera-CBD has also been shown to have anti-inflammatory effects. For more information, visit . Cautionary Statement Regarding Forward-Looking Statements This press release may contain forward-looking statements. These forward-looking statements involve known and unknown risks, uncertainties and other factors which may cause actual results, performance, or achievements to be materially different from any expected future results, performance, or achievements. Forward-looking statements speak only as of the date they are made and none of MyMD nor its affiliates assume any duty to update forward-looking statements. Words such as “anticipate,” “believe,” “could,” “estimate,” “expect,” “may,” “plan,” “will,” “would’’ and other similar expressions are intended to identify these forward-looking statements. Important factors that could cause actual results to differ materially from those indicated by such forward-looking statements include, without limitation: the timing of, and MyMD’s ability to, obtain and maintain regulatory approvals for clinical trials of MyMD’s pharmaceutical candidates; the timing and results of MyMD’s planned clinical trials for its pharmaceutical candidates; the amount of funds MyMD requires for its pharmaceutical candidates; increased levels of competition; changes in political, economic or regulatory conditions generally and in the markets in which MyMD operates; MyMD’s ability to retain and attract senior management and other key employees; MyMD’s ability to quickly and effectively respond to new technological developments; MyMD’s ability to protect its trade secrets or other proprietary rights, operate without infringing upon the proprietary rights of others and prevent others from infringing on MyMD’s proprietary rights; and the impact of the COVID-19 pandemic or similar public health emergencies on MyMD’s results of operations, business plan and the global economy. A discussion of these and other factors with respect to MyMD is set forth in the Company’s Annual Report on Form 10-K for the year ended December 31, 2022, filed by MyMD on March 31, 2023, as may be supplemented or amended by the Company’s Quarterly Reports on Form 10-Q. Forward-looking statements speak only as of the date they are made and MyMD disclaims any intention or obligation to revise any forward-looking statements, whether as a result of new information, future events or otherwise. 1 Reference: TRPV1 is a non-selective cation channel; when it is activated by capsaicin, sodium and calcium ions flowing through TRPV1 into the cell to depolarize nociceptive neurons, leading to action potential firing and finally the sensation of spiciness (Caterina et al., 1997).