GPR158

Pictured: Pills spilling out of bottle/artisteer/i artisteer/Getty Images/iStockphoto New therapeutics for Major Depressive Disorder could change the treatment landscape and give patients more options. Pictured: Pills spilling out of bottle/artisteer/iStock A common amino acid, glycine , can signal the brain to slow down, likely an operational variable in major depression, anxiety and other mood disorders, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology discovered recently . The discovery, first reported by Science , improves understanding of the biological causes of major depressive disorder (MDD) and could speed up efforts to develop new, faster-acting medications and therapeutics for MDD, neuroscientist Kirill Martemyanov, Ph.D., author of the study, told BioSpace in an email. “Glycine effects are non-specific,” he said. “It engages a range of targets and is also a building block of proteins, hence [it’s] metabolized easily.” He added that there is a need for specific small-molecule drugs targeting G protein-coupled receptor 158 (GPR158), which binds to glycine. Martemyanov’s team suspected GPR158 might play a role in the development of MDD, possibly by influencing the function of key neurotransmitter systems in the brain, such as the serotonin and dopamine system. Soon, he led a team to publish data confirming this was the case. Once he understood the role of the gene, he investigated how sensors on brain cells receive and transmit signals. Martemyanov said the signaling molecule wasn’t an activator in the cell as previously thought, but an inhibitor. His team found that GPR158 connected to a partnering molecule slowed signaling rather than speeding it up when bound to glycine. His team renamed GPR158 to mGlyR, short for metabotropic glycine receptor, found to be highly active in the brain’s medial prefrontal cortex. “We also need to understand where exactly mGlyR is engaged and how it is regulated in the brain to produce effects on mood,” he said. Traditional Medication-Based Treatments The World Health Organization describes MDD as an epidemic that, within two decades, will be second to cardiovascular disease in terms of global disease burden. In 2021, the CDC estimated MDD exacts an economic burden of $326 billion annually in the U.S. Even then, this figure doesn’t wholly account for the fallout of rising diagnoses of MDD concurrent with the pandemic, wherein the WHO estimated rates of MDD increased by 25% worldwide. Traditional medication -assisted treatment options for MDD often take weeks or months to land on a drug that works well with an individual’s body chemistry sufficiently to take effect and show efficacy. Most traditional approaches are grouped into four categories : Selective serotonin reuptake inhibitors (SSRIs): increase levels of serotonin in the brain Serotonin-norepinephrine reuptake inhibitors (SNRIs): increase levels of serotonin and norepinephrine in the brain Tricyclic antidepressants (TCAs): block the reuptake of serotonin and norepinephrine, which increases the levels of these neurotransmitters Monoamine oxidase inhibitors (MAOIs): inhibit the action of an enzyme called monoamine oxidase, which breaks down neurotransmitters (serotonin, norepinephrine, and dopamine) Breakthrough Therapeutics Like Martemynanov, another expert hopes patients won’t have to rely on a “wait and see” approach as is often used in the traditional medication approach to treating MDD. Seth Lederman Seth Lederman , CEO of Tonix Pharmaceuticals , said finding new ways to approach MDD is imperative because of how deeply the condition affects society. “From a societal point of view, it’s hard to argue that there’s any more important thing to work on, considering that brain drugs relate to suicide, homelessness and a large portion of criminality,” he told BioSpace . Lederman and New Jersey-based-Tonix are working to re-examine drugs approved in Europe and perhaps overlooked in the U.S. in favor of the big four categories of MDD meds to revisit treatment options first broached decades ago. He said the “dogma” about treating depression in the U.S. might hold back research into more effective approaches. While investigating drugs to treat fibromyalgia, Lederman said he lasered in on tianeptine , a drug available in the EU and other parts of the world for decades. He’s particularly interested in how the drug can encourage dendritic arborization in a way the four major classes of MDD drugs do not. “In the brains of depressed people … neurons shrink and undergo attrition,” he said. “There’s lower connectivity in their brains.” Lederman noted that thus far, tianeptine not only positively affects neuroplasticity by fostering arborization, but also stacks up with traditional MMD drugs in terms of efficacy, with fewer undesirable side effects, like weight gain or sexual dysfunction. Tonix’s once-daily formulation of TNX-601 ER was designed to be bioequivalent to the three-times-a-day formulation of tianeptine sodium immediate-release tablets available overseas. No tianeptine-containing product has been approved by the FDA at this time for U.S. markets. The drug, under the name TNX-601 ER, is currently being trialed in Phase II as a monotherapy. “It’s a very exciting time in depression,” Lederman said of the biopharma landscape. “Part of what has made it so exciting is that people have been laboring under this cloud, this yoke, constrained by the idea that modulating neurotransmitters was the only way.” Besides Tonix’s approach, other biopharmas are also working to flip the script on the traditional drugging paradigm. Genetika+, based in Israel, uses blood cells and stem cell technology to assess an individual’s unique biomarkers via a blood sample. The result is a “ Brain-in-a-Dish ” technology, wherein the patient’s sample is tested against more than 70 approved antidepressants and drug combinations to predict which drug will be the most efficacious for each individual. Talia Cohen Solal, Ph.D. Talia Cohen Solal, the company’s CEO and co-founder, told BioSpace this approach will expedite drug treatment by helping physicians make the right drug choice quickly. “This is the first time you can take almost like a cancer biopsy, but now you can actually see what’s going on,” Cohen Solal said. “In the closest model, we have the patient’s brain, and then you can expose that sample to different antidepressants and see which antidepressant has the strongest impact on patients in your own population.” She agreed with Lederman that increasing connectivity in the brain is the golden ticket to finding drugs that work—and can be delivered to the patient quickly, unlike in traditional drugging. “When people are suffering from depression from different types of studies, you see this one can see a reduction in connectivity,” she said. “Restoring that connectivity is basically the biomarker we seek.” What’s more, she said 67% of depression sufferers end up trying multiple medications. “There’s around 20 million people suffering from depression in the United States every year. Only 10 million get access to care. By reducing that and getting those people straight into the right medication, and out of the [health care] system, that will free up space for other people to get access to better mental health care, and really improve outcomes.” Solal Cohen expected Genetika+’s approach to be covered by American health insurance, as with other genetic testing. The approach remains in clinical trials in the U.S. with plans to launch the testing for American MDD patients in 2024. Lisa Munger is a senior editor at BioSpace. You can reach her at lisa.munger@biospace.com. Follow her on LinkedIn .

Pictured: Pills spilling out of bottle/artisteer/iStock A common amino acid, glycine, can signal the brain to slow down, likely an operational variable in major depression, anxiety and other mood disorders, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology discovered recently. The discovery, first reported by Science, improves understanding of the biological causes of major depressive disorder (MDD) and could speed up efforts to develop new, faster-acting medications and therapeutics for MDD, neuroscientist Kirill Martemyanov, Ph.D., author of the study, told BioSpace in an email. “Glycine effects are non-specific, he said. “It engages a range of targets and is also a building block of proteins, hence [it's] metabolized easily." He added that there is a need for specific small-molecule drugs targeting G protein-coupled receptor 158 (GPR158), which binds to glycine. Martemyanov’s team suspected GPR158 might play a role in the development of MDD, possibly by influencing the function of key neurotransmitter systems in the brain, such as the serotonin and dopamine system. Soon, he led a team to publish data confirming this was the case. Once he understood the role of the gene, he investigated how sensors on brain cells receive and transmit signals. Martemyanov said the signaling molecule wasn’t an activator in the cell as previously thought, but an inhibitor. His team found that GPR158 connected to a partnering molecule slowed signaling rather than speeding it up when bound to glycine. His team renamed GPR158 to mGlyR, short for metabotropic glycine receptor, found to be highly active in the brain’s medial prefrontal cortex. “We also need to understand where exactly mGlyR is engaged and how it is regulated in the brain to produce effects on mood,” he said. Traditional Medication-Based Treatments The World Health Organization describes MDD as an epidemic that, within two decades, will be second to cardiovascular disease in terms of global disease burden. In 2021, the CDC estimated MDD exacts an economic burden of $326 billion annually in the U.S. Even then, this figure doesn’t wholly account for the fallout of rising diagnoses of MDD concurrent with the pandemic, wherein the WHO estimated rates of MDD increased by 25% worldwide. Traditional medication-assisted treatment options for MDD often take weeks or months to land on a drug that works well with an individual’s body chemistry sufficiently to take effect and show efficacy. Most traditional approaches are grouped into four categories: Selective serotonin reuptake inhibitors (SSRIs): increase levels of serotonin in the brain Serotonin-norepinephrine reuptake inhibitors (SNRIs): increase levels of serotonin and norepinephrine in the brain Tricyclic antidepressants (TCAs): block the reuptake of serotonin and norepinephrine, which increases the levels of these neurotransmitters Monoamine oxidase inhibitors (MAOIs): inhibit the action of an enzyme called monoamine oxidase, which breaks down neurotransmitters (serotonin, norepinephrine, and dopamine) Breakthrough Therapeutics Like Martemynanov, another expert hopes patients won’t have to rely on a “wait and see” approach as is often used in the traditional medication approach to treating MDD. Seth Lederman Seth Lederman, CEO of Tonix Pharmaceuticals, said finding new ways to approach MDD is imperative because of how deeply the condition affects society. “From a societal point of view, it's hard to argue that there's any more important thing to work on, considering that brain drugs relate to suicide, homelessness and a large portion of criminality,” he told BioSpace. Lederman and New Jersey-based-Tonix are working to re-examine drugs approved in Europe and perhaps overlooked in the U.S. in favor of the big four categories of MDD meds to revisit treatment options first broached decades ago. He said the “dogma” about treating depression in the U.S. might hold back research into more effective approaches. While investigating drugs to treat fibromyalgia, Lederman said he lasered in on tianeptine, a drug available in the EU and other parts of the world for decades. He’s particularly interested in how the drug can encourage dendritic arborization in a way the four major classes of MDD drugs do not. “In the brains of depressed people … neurons shrink and undergo attrition,” he said. “There's lower connectivity in their brains.” Lederman noted that thus far, tianeptine not only positively affects neuroplasticity by fostering arborization, but also stacks up with traditional MMD drugs in terms of efficacy, with fewer undesirable side effects, like weight gain or sexual dysfunction. Tonix’s once-daily formulation of TNX-601 ER was designed to be bioequivalent to the three-times-a-day formulation of tianeptine sodium immediate-release tablets available overseas. No tianeptine-containing product has been approved by the FDA at this time for U.S. markets. The drug, under the name TNX-601 ER, is currently being trialed in Phase II as a monotherapy. “It’s a very exciting time in depression,” Lederman said of the biopharma landscape. “Part of what has made it so exciting is that people have been laboring under this cloud, this yoke, constrained by the idea that modulating neurotransmitters was the only way.” Besides Tonix’s approach, other biopharmas are also working to flip the script on the traditional drugging paradigm. Genetika+, based in Israel, uses blood cells and stem cell technology to assess an individual’s unique biomarkers via a blood sample. The result is a “Brain-in-a-Dish” technology, wherein the patient’s sample is tested against more than 70 approved antidepressants and drug combinations to predict which drug will be the most efficacious for each individual. Talia Cohen Solal Talia Cohen Solal, the company's CEO and co-founder, told BioSpace this approach will expedite drug treatment by helping physicians make the right drug choice quickly. “This is the first time you can take almost like a cancer biopsy, but now you can actually see what's going on,” Cohen Solal said. “In the closest model, we have the patient's brain, and then you can expose that sample to different antidepressants and see which antidepressant has the strongest impact on patients in your own population.” She agreed with Lederman that increasing connectivity in the brain is the golden ticket to finding drugs that work—and can be delivered to the patient quickly, unlike in traditional drugging. “When people are suffering from depression from different types of studies, you see this one can see a reduction in connectivity,” she said. “Restoring that connectivity is basically the biomarker we seek.” What’s more, she said 67% of depression sufferers end up trying multiple medications. “There's around 20 million people suffering from depression in the United States every year. Only 10 million get access to care. By reducing that and getting those people straight into the right medication, and out of the [health care] system, that will free up space for other people to get access to better mental health care, and really improve outcomes.” Solal Cohen expected Genetika+’s approach to be covered by American health insurance, as with other genetic testing. The approach remains in clinical trials in the U.S. with plans to launch the testing for American MDD patients in 2024. Lisa Munger is a senior editor at BioSpace. You can reach her at lisa.munger@biospace.com. Follow her on LinkedIn.

The simple amino acid glycine looks to be a previously unknown contributor to depression. A common amino acid, glycine, can deliver a "slow-down" signal to the brain, likely contributing to major depression, anxiety and other mood disorders in some people, scientists at the Wertheim UF Scripps Institute for Biomedical Innovation & Technology have found. The discovery, outlined Thursday in the journal Science, improves understanding of the biological causes of major depression and could accelerate efforts to develop new, faster-acting medications for such hard-to-treat mood disorders, said neuroscientist Kirill Martemyanov, Ph.D., corresponding author of the study. "Most medications for people with depression take weeks before they kick in, if they do at all. New and better options are really needed," said Martemyanov, who chairs the neuroscience department at the institute in Jupiter. Major depression is among the world's most urgent health needs. Its numbers have surged in recent years, especially among young adults. As depression's disability, suicide numbers and medical expenses have climbed, a study by the U.S. Centers for Disease Control and Prevention in 2021 put its economic burden at $326 billion annually in the United States. Martemyanov said he and his team of students and postdoctoral researchers have spent many years working toward this discovery. They didn't set out to find a cause, much less a possible treatment route for depression. Instead, they asked a basic question: How do sensors on brain cells receive and transmit signals into the cells? Therein lay the key to understanding vision, pain, memory, behavior and possibly much more, Martemyanov suspected. "It's amazing how basic science goes. Fifteen years ago we discovered a binding partner for proteins we were interested in, which led us to this new receptor," Martemyanov said. "We've been unspooling this for all this time." In 2018 the Martemyanov team found the new receptor was involved in stress-induced depression. If mice lacked the gene for the receptor, called GPR158, they proved surprisingly resilient to chronic stress. That offered strong evidence that GPR158 could be therapeutic target, he said. But what sent the signal? A breakthrough came in 2021, when his team solved the structure of GPR158. What they saw surprised them. The GPR158 receptor looked like a microscopic clamp with a compartment -- akin to something they had seen in bacteria, not human cells. "We were barking up the completely wrong tree before we saw the structure," Martemyanov said. "We said, 'Wow, that's an amino acid receptor. There are only 20, so we screened them right away and only one fit perfectly. That was it. It was glycine." That wasn't the only odd thing. The signaling molecule was not an activator in the cells, but an inhibitor. The business end of GPR158 connected to a partnering molecule that hit the brakes rather than the accelerator when bound to glycine. "Usually receptors like GPR158, known as G protein Coupled Receptors, bind G proteins. This receptor was binding an RGS protein, which is a protein that has the opposite effect of activation," said Thibaut Laboute, Ph.D., a postdoctoral researcher from Martemyanov's group and first author of the study. Scientists have been cataloging the role of cell receptors and their signaling partners for decades. Those that still don't have known signalers, such as GPR158, have been dubbed "orphan receptors." The finding means that GPR158 is no longer an orphan receptor, Laboute said. Instead, the team renamed it mGlyR, short for "metabotropic glycine receptor." "An orphan receptor is a challenge. You want to figure out how it works," Laboute said. "What makes me really excited about this discovery is that it may be important for people's lives. That's what gets me up in the morning." Laboute and Martemyanov are listed as inventors on a patent application describing methods to study GPR158 activity. Martemyanov is a cofounder of Blueshield Therapeutics, a startup company pursuing GPR158 as a drug target. Glycine itself is sold as a nutritional supplement billed as improving mood. It is a basic building block of proteins and affects many different cell types, sometimes in complex ways. In some cells, it sends slow-down signals, while in other cell types, it sends excitatory signals. Some studies have linked glycine to the growth of invasive prostate cancer. More research is needed to understand how the body maintains the right balance of mGlyR receptors and how brain cell activity is affected, he said. He intends to keep at it. "We are in desperate need of new depression treatments," Martemyanov said. "If we can target this with something specific, it makes sense that it could help. We are working on it now." The research was supported by the National Institute of Health's National Institute of Mental Health (MH105482) and National Institute of General Medical Sciences (GM069832).