Cav2.2

Researchers studied the effects of their compound, CBD3063, in multiple models of acute and chronic pain. A small molecule alleviates four different types of acute and chronic pain in rodents, so far with none of the side effects associated with widely prescribed non-opioid painkiller gabapentin. In an article published Nov. 13 in Proceedings of the National Academy of Sciences, researchers from New York University described how they discovered their compound, dubbed CBD3063, and tested it in models of injury- and chemotherapy-induced neuropathy, trigeminal nerve pain and inflammatory pain. They hope to eventually take it to the clinic. “The compound can be given [via] multiple routes, it works in different species—mice and rats—and in males and females,” senior author Rajesh Khanna, Ph.D., who is also working on a gene therapy for chronic pain, told Fierce Biotech Research in an interview. “No toxicity has been seen, and it works across an array of pain conditions. That’s really the crux of this paper.” CBD3063, gabapentin and pregabalin all ultimately exert their effects through their interactions with a calcium channel called Cav2.2 on pain-sensing neurons, but they do so via different mechanisms. Where gabapentin acts on the outside of the channel, CBD3063 alters it from the inside by stopping a protein called CRMP2 from binding to it. Decoupling the two keeps calcium from entering the channel, which ultimately leads to less neurotransmitter release—and pain reduction. Khanna’s lab first discovered the peptide that would become the basis for CBD3063 back in 2011. Since then, the team has worked on formulating it into a small molecule, figuring out that they could take the number of necessary amino acids down from 15 to just two and pairing those with a protein taken from the HIV virus to help it get into cells. As part of the new study, they worked with the University of Pittsburgh to run a large screen of 27 million existing drug compounds to see whether any had the same composition. The results led them to CBD3063. After a barrage of cell studies to show that the compound did indeed inhibit CRMP2 and was highly selective for Cav2.2—an important consideration, as drugs for arrhythmias and hypertension target similar channels—the researchers tested it in double-blinded experiments on a mouse model of nerve injury, assessing it head-to-head with gabapentin. They found that mice who received the compound were less debilitated by pain than untreated mice. On top of that, CBD3063 worked at a fraction of gabapentin’s effective dose.  “We were getting the same amount of relief [with 1 to 10 milligrams per kilogram of CBD3063] that the clinically available compound gabapentin was producing at 30 milligrams per kilogram,” Khanna said. “That’s very important, because now we are comparing it to a clinical benchmark.” The researchers then conducted experiments on rodents that had nerve damage caused by treatment with paclitaxel, a chemotherapy drug. After giving four doses of paclitaxel over eight days, the researchers waited for the animals to develop nerve damage and an aversion to cold, another common symptom experienced by people who undergo chemotherapy. When the animals developed symptoms two or three weeks later, the team gave them single doses of CBD3063. “We saw a beautiful reversal of both nerve pain and cold aversion,” Khanna said. Next, the researchers looked at how well the drug could control orofacial pain. Until this set of experiments, the scientists had been giving the drug through the animals’ abdomens via what’s known as intraperitoneal delivery. This time, they tried giving it intranasally, thinking that a nasal spray formulation would be ideal for this kind of scenario. “It also bypasses the blood-brain barrier, and it goes right into the regions it needs to,” Khanna said. Once again, the drug worked: It relieved pain consistent with the expected half-life of the compound in such a formulation, he said, which is a little more than three hours. His team then moved to their final models. An assessment of whether CBD3063 could relieve chronic pain from inflammatory conditions like arthritis showed that single injections of the drug into mice with paw inflammation relieved their pain for at least four hours afterward. And an experiment on rats with a chronic nerve injury showed that they didn’t develop tolerance to the drug even with multiple injections over a two-week period. But the researchers weren’t done yet: They wanted to be sure that CBD3063 didn’t block out unrelated types of pain or replicate gabapentin’s side effects, which include memory loss, mood changes, lethargy and more. Experiments on uninjured mice showed that the drug had no effect on types of pain that were unrelated to the type of neuropathy it was designed to treat. Meanwhile, gabapentin seemed to make mice less responsive to important acute pain signals. As for side effects, the scientists found that abdominal injections of CBD3063 had no impact on rodents’ memory or cognition—unlike gabapentin, which dramatically diminished their ability to recognize objects. Their compound also had no effects on the animals’ cardiovascular function, which case studies suggest may be impacted by gabapentin. “This demonstrates that CBD3063 preserves that adaptive role of pain without causing any kind of neurological side effects,” Khanna said. “That’s really the benefit.” There’s still a long road to the clinic. The researchers will need to do many more experiments to understand the drug’s long-term effects as well as whether tolerance eventually arises. And while CBD3063 has never been used for pain relief, it is not technically a new compound. Thus, Khanna’s team will need to substantially transform and optimize it before they can patent it, then will need to partner with a pharmaceutical company to take it into development, he said. “I don’t want to provide any false hope, because the path to humans is three to five years away at the very least,” Khanna said. “In order to get there, there’s a huge journey ahead.”

A compound -- one of 27 million screened in a library of potential new drugs -- reversed four types of chronic pain in animal studies, according to new research. The small molecule, which binds to an inner region of a calcium channel to indirectly regulate it, outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain. A compound -- one of 27 million screened in a library of potential new drugs -- reversed four types of chronic pain in animal studies, according to new research led by NYU College of Dentistry's Pain Research Center and published in the Proceedings of the National Academy of Sciences (PNAS). The small molecule, which binds to an inner region of a calcium channel to indirectly regulate it, outperformed gabapentin without troublesome side effects, providing a promising candidate for treating pain. Calcium channels play a central role in pain signaling, in part through the release of neurotransmitters such as glutamate and GABA -- "the currency of the pain signal," according to Rajesh Khanna, director of the NYU Pain Research Center and professor of molecular pathobiology at NYU Dentistry. The Cav2.2 (or N-type) calcium channel is the target for three clinically available drugs, including gabapentin (sold under brand names including Neurontin) and pregabalin (Lyrica), which are widely used to treat nerve pain and epilepsy. Gabapentin mitigates pain by binding to the outside of the Cav2.2 calcium channel, affecting the channel's activity. However, like many pain medications, gabapentin use often comes with side effects. "Developing effective pain management with minimal side effects is crucial, but creating new therapies has been challenging," said Khanna, the senior author of the PNAS study. "Rather than directly going after known targets for pain relief, our lab is focused on indirectly targeting proteins that are involved in pain." Inside the channel Khanna has long been interested in a protein called CRMP2, a key regulator of the Cav2.2 calcium channel that binds to the channel from the inside. He and his colleagues previously discovered a peptide (a small region of amino acids) derived from CRMP2 that could uncouple CRMP2 from the calcium channel. When this peptide -- dubbed the calcium channel-binding domain 3, or CBD3 -- was delivered to cells, it acted as a decoy, blocking CRMP2 from binding to the inside of the calcium channel. This resulted in less calcium entering the calcium channel and less neurotransmitter release, which translated to less pain in animal studies. Peptides are difficult to synthesize as drugs because they are short-acting and easily degrade in the stomach, so the researchers sought to create a small molecule drug based on CBD3. Starting with the 15 amino acids that make up the CBD3 peptide, they honed in on two amino acids that studies showed were responsible for inhibiting calcium influx and mitigating pain. "At that point, we realized that these two amino acids could be the building blocks for designing a small molecule," said Khanna. From 27 million to one In collaboration with colleagues at the University of Pittsburgh, the researchers ran a computer simulation that screened a library of 27 million compounds to look for a small molecule that would "match" the CBD3 amino acids. The simulation narrowed the library down to 77 compounds, which the researchers experimentally tested to see if they lessened the amount of calcium influx. This further pared the pool down to nine compounds, which were assessed using electrophysiology to measure decreases in electrical currents through the calcium channels. One compound, which the researchers named CBD3063, emerged as the most promising candidate for treating pain. Biochemical tests revealed that CBD3063 disrupted the interaction between the CaV2.2 calcium channel and CRMP2 protein, reduced calcium entering the channel, and lessened the release of neurotransmitters. "Many scientists have screened the same library of compounds, but have been trying to block the calcium channel from the outside. Our target, these two amino acids from CRMP2, is on the inside of the cell, and this indirect approach may be the key to our success," said Khanna. Four labs, four types of pain Khanna's lab then tested CBD3063 with mouse models for pain related to injury. The compound was effective in alleviating pain in both male and female mice -- and notably, in a head-to-head test with the drug gabapentin, the researchers needed to use far less CBD3063 (1 to 10 mg) than gabapentin (30 mg) to reduce pain. To explore whether CBD3063 helped with different types of chronic pain, Khanna partnered with researchers at Virginia Commonwealth University, Michigan State University, and Rutgers University. Collaborators ran similar studies administering CBD3063 to treat animal models of chemotherapy-induced neuropathy, inflammatory pain, and trigeminal nerve pain -- all successfully reversing pain, similar to gabapentin. But unlike gabapentin, the use of CBD3063 did not come with side effects, including sedation, changes to cognition such as memory and learning, or changes to heart rate and breathing. What's next The researchers are continuing to study CBD3063, refining its chemical composition and running additional tests to study the compound's safety and assess if tolerance develops. Long-term, they hope to bring a CBD3063-derived drug to clinical trials in an effort to offer new options for safe and effective pain relief. "Identifying this first-in-class small molecule has been the culmination of more than 15 years of research. Though our research journey continues, we aspire to present a superior successor to gabapentin for the effective management of chronic pain," said Khanna. Additional authors include Kimberly Gomez, Tyler Nelson, Heather Allen, Aida Calderon-Rivera, Sara Hestehave, Erick Rodríguez Palma, Paz Duran, Santiago Loya-Lopez, Samantha Perez-Miller, and May Khanna of NYU Dentistry's Pain Research Center; Elaine Zhu and Jing Wang of NYU Grossman School of Medicine; Handoko and Paramjit Arora of NYU's Department of Chemistry; Ulises Santiago and Carlos Camacho of the University of Pittsburgh; Yuan Zhou, Angie Dorame, and Aude Chefdeville of the University of Arizona; Upasana Kumar, Rory Shields, Wanhong Zuo, Huijuan Hu, and Olga Korczeniewska of Rutgers University; Eda Koseli, Bryan McKiver, and M. Imad Damaj of Virginia Commonwealth University; Denise Giuvelis and Tamara King of the University of New England; Kufreobong Inyang and Geoffroy Laumet of Michigan State University; Dongzhi Ran, Yi Lu, and Xia Liu of Chongqing Medical University; Marcel Patek of Bright Rock Path LLC; and Aubin Moutal of St. Louis University. The research labs are supported in part by the National Institutes of Health (NS098772, NS120663, DA042852, NS119263, GM115384, NS121776, NS121259, P30GM145497, and R01CA219637).

Calgary, Alberta--(News - October 19, 2022) - Hemostemix Inc. (TSXV: HEM) (OTCQB: HMTXF) (FSE: 2VFO) ("Hemostemix" or the "Company") and its wholly-owned subsidiary, PreCerv Inc., are pleased to announce the commencement of PreCerv Inc.'s study of NCP-01. The spinal cord injury repair study will focus on the improvement of motor function and the decrease of pain following the injection of NCP-01 into the spinal fluid pathway of small animals. The global neuropathic pain market was $10.2 Billion in 2020, according to data and analytics company, Global Data, and it is forecast to grow at a CAGR of 12.5% to $25 Billion by 2027. In three studies of 91 subjects, ACP-01 is reported to significantly decrease pain associated with critical limb ischemia and peripheral arterial disease. In combination with NCP-01, which will target improved motor function, ACP-01+NCP-01 are poised to be the leading patient-sourced solution to treat neuropathic pain and motor function. "ACP-01 increases blood flow to areas that signal a need for revitalized circulation. That decreases pain. Combining ACP-01 with NCP-01 potentially creates the best way to decrease pain and increase functionality," stated Thomas Abraham, President, PreCerv Inc. "PreCerv Inc. is going to market in parallel with Hemostemix Inc. As discussed at the shareholders meeting, Mr. Abraham and I are working on a transaction to spin out PreCerv Inc. to the shareholders of Hemostemix Inc. as a return of capital," stated Thomas Smeenk, CEO. NCP-01 are the patient's own (autologous) neuronal cell precursors. Like ACP-01, NCP-01 are generated from the patient's blood, a second derivation of the Company's patented synergetic cell population. NCPs express the neural progenitor markers Nestin and bIII-Tubulin, typical of newly differentiated neurons and Neu-N, a nuclear protein present in neurons. Other cells from these cultures expressed O4 and GFAP, oligodendrocyte and astrocyte markers. Flow cytometry analysis showed that 49.4% ± 6.4% and 34% ± 5.9% of NCPs expressed Nestin and bIII-Tubulin respectively. In addition to demonstrating neural lineage, differentiated NCPs responded to the neurotransmitters glutamate and GABA, as detected by calcium influx through voltage-gated calcium channels. ABOUT HEMOSTEMIX Hemostemix is an autologous stem cell therapy company, founded in 2003. A winner of the World Economic Forum Technology Pioneer Award, the Company has developed, patented, and is scaling a patient's blood-based stem cell therapeutics platform that includes angiogenic cell precursors, neuronal cell precursor and cardiomyocyte cell precursors. Seven studies including 260 ACP-01 recipients define its safety and efficacy pro a treatment for heart diseases such as Dilated and Ischemic Cardiomyopathy, Angina, and diseases of Ischemia such as Critical Limb Ischemia. The Company owns 91 patents across five patent families. For more information, please visit For further information, please contact: Thomas Smeenk, President, CEO & Co-Founder EM: tsmeenk@hemostemix.com PH: 905-580-4170 Thomas Abraham, President, PreCerv Inc. EM: tabraham@hemostemix.com PH: 647-461-7169 Neither the TSX Venture Exchange nor its Regulation Service Provider (as that term is defined under the policies of the TSX Venture Exchange) accepts responsibility for the adequacy or accuracy of this release. Forward-Looking Information: This news release contains "forward-looking information" within the meaning of applicable Canadian securities legislation. All statements, other than statements of historical fact, included herein are forward-looking information. In particular, this news release contains forward-looking information in relation to: the study of NCP-01 as a treatment of pain and increased motor function, the combination of ACP-01 and NCP-01 as a treatment. ‎‎There can be no assurance that such forward-looking information will prove to be accurate. Actual results and future events could differ materially from those anticipated in such forward-looking information. This forward-looking information reflects Hemostemix's current beliefs and is based on information currently available to Hemostemix and on assumptions Hemostemix believes are reasonable. These assumptions include, but are not limited to: the underlying value of Hemostemix and its Common Shares; the successful resolution of the litigation that Hemostemix is pursuing or defending (the "Litigation"); the results of ACP-01 research, trials, studies and analyses, including the analysis being equivalent to or better than previous research, trials or studies; the receipt of all required regulatory ‎approvals for research, trials or studies; the level of activity, market acceptance and market trends in the healthcare sector; the ‎economy generally; consumer ‎interest in Hemostemix's services and products; competition and ‎Hemostemix's competitive advantages; and Hemostemix obtaining satisfactory financing to ‎ fund Hemostemix's operations including any research, trials or studies, and any Litigation. Forward-looking information is Subject to known and unknown risks, uncertainties and other factors that may cause the actual results, level of activity, performance or achievements of Hemostemix to be materially different from those expressed or implied by such forward-looking information. Such risks and other factors may include, but are not limited to: the ability of Hemostemix to complete clinical trials, complete a satisfactory analyses and results of such analyses to gain regulatory approval of a phase II or phase III clinical trial of ACP-01; potential litigation Hemostemis mayface; general business, economic, competitive, political and social uncertainties; general capital market conditions and market prices for securities; delay or failure to receive board or regulatory approvals; the actual results of future operations including the actual results of future research, trials or studies; competition; changes in legislation ‎affecting Hemostemix; the timing and availability of external financing on acceptable terms; long-term capital requirements and future developments in Hemostemix's markets and the markets in which it expects to compete;‎ lack of qualified, skilled labour or loss of key individuals; and risks ‎related to the COVID-19 pandemic including various recommendations, orders and measures of governmental authorities to ‎try to limit the pandemic, including travel restrictions, border closures, non-essential business closures service disruptions, quarantines, self-isolations, shelters-in-place and social distancing, disruptions to markets, disruptions to economic activity and ‎financings, disruptions to supply chains and sales channels, and a deterioration of general economic conditions including a ‎possible national or global recession or depression;the potential impact that the COVID-19 pandemic may have on Hemostemix which may include a decreased demand for the services that Hemostemix offers; and a deterioration of financial markets that could limit Hemostemix's ability to obtain external financing. A description of additional risk factors that may cause actual results to differ materially from forward-looking information can be found in Hemostemix's disclosure documents on the SEDAR website at . Although Hemostemix has attempted to identify important factors that could cause actual results to differ materially from those contained in forward-looking information, there may be other factors that cause results not to be as anticipated, estimated or intended. Readers are cautioned that the foregoing list of factors is not exhaustive. Readers are further cautioned not to place undue reliance on forward-looking information as there can be no assurance that the plans, intentions or expectations upon which they are placed will occur. Forward-looking information contained in this news release is expressly qualified by this cautionary statement. The forward-looking information contained in this news release represents the expectations of Hemostemix as of the date of this news release and, accordingly, it is Subject to change after such date. However, Hemostemix expressly disclaims any intention or obligation to update or revise any forward-looking information, whether as a result of new information, future events or otherwise, except as expressly required by applicable securities law. To view the source version of this press release, please visit