Utah researchers report significant new insights into the development of blood cancers. In work published today in Blood Cancer Discovery, a journal of the American Association for Cancer Research, scientists describe an analysis of published data from more than 7,000 patients diagnosed with leukemia and other blood disorders. Their findings provide new clues about mutations that may initiate cancer development and those that may help cancer to progress.
The researchers sought to identify mutation hotspots, or frequent changes in specific locations of the cancer patients’ genetic information. The researchers then used these hotspots to look for whether the same mutations were present in the DNA data of more than 4,500 people who were not known to have a cancer diagnosis. They found that approximately 2 percent of these presumably healthy participants had, at low levels, mutations identical to those frequently observed in the cancer patients.
“Understanding how a disease develops is greatly benefited by studying persons who are currently healthy but are on a trajectory for disease onset,” said Clint Mason, PhD, assistant professor of pediatrics at the U of U, who specializes in cancer genomics and bioinformatics and led the study.
Mutations occur throughout the 3 billion bases of DNA that are present in human cells. Many will have no impact on health, yet certain mutations may cause or support development of diseases, including cancer. Therefore, scientists are working to discern which mutations have a significant impact on health. In this study, the researchers sought to understand which mutations are most frequently present in adults and children both with and without blood cancers. They hope this information may illuminate an understanding of these cancers, and further, may potentially be used to identify people who are progressing towards cancer.
The team of researchers consisted nearly entirely of University of Utah (U of U) faculty and students. Mason was joined by co-first authors Julie Feusier, PhD, a trainee in the department of human genetics and now a postdoctoral fellow at Huntsman Cancer Institute, and Sasi Arunachalam, PhD, a postdoctoral fellow at Huntsman Cancer Institute and now a research associate at St. Jude Children’s Research Hospital, in performing analyses along with other co-authors.
For the first part of the study, the researchers completed a large data mining analysis to examine published data from 48 cancer studies that reported mutations present in persons who were being diagnosed with leukemia or other hematologic malignancies. Across the 7,430 pediatric and adult cancer patients of those studies, 434 DNA locations were identified as frequently mutated. Then, in a subsequent analysis of many terabytes of publicly available genetic data, the researchers identified these same cancer-relevant mutations at low levels among 83 of the 4,538 persons who were presumably free from cancer.
“When identical mutations are found to be present in a small percentage of blood cells of a healthy person, it may indicate that something abnormal has begun to occur,” explained Mason.
This abnormal process (known as clonal hematopoiesis) has previously been found to be increasingly common as people age. As a result, researchers generally focus on the study of adults when investigating this phenomenon. Yet in this study, in addition to adults, the researchers analyzed data from 400 children who were likely to be free from cancer. They found preliminary evidence that early cancer mutations could be detected in this age group.
In an accompanying commentary, to be published by Blood Cancer Discovery in its “In the Spotlight” section, Barbara Spitzer, MD, and Ross Levine, MD, of the Memorial Sloan Kettering Cancer Center, wrote, “This work demonstrates the first evidence that [clonal hematopoiesis] is observed in children outside of those with advanced malignancies.” They further commented, “This expansion of the range of hematologic malignancy hotspot mutations goes beyond an improved understanding of the molecular repertoire of hematologic malignancies… More complete knowledge of relevant mutations may increase our detection of patients at highest risk for malignant transformation.”
Finding a low-level mutation identical to one that is frequently present at cancer diagnoses could be alarming to a currently healthy person screened for such events. But fortunately, because cancer frequently requires multiple mutations to be present in a sizeable fraction of cells, most persons with a single low-level mutation are not likely to develop cancer for many years or decades — if they develop cancer at all. Large longitudinal studies are needed to identify the timeframe over which specific mutations or combinations of mutations accelerate progression to cancer.
The Utah researchers next hope to determine the stability of mutations identified at younger ages. This will give a preliminary glimpse into their potential to serve as biomarkers for those having greatest risk of cancer. Future intervention studies will require such an identification.
“Our goal has been to help fill in gaps in the understanding of cancer development so that future prevention work can take place more quickly and effectively,” said Mason. “We are grateful to have been able to contribute a few puzzle pieces to that monumental effort.”

A new study led by Belgian and Spanish researchers published in Scientific Reports adds evidence about the potential benefits of green tea extracts in Down syndrome. The researchers observed that the intake of green tea extracts can reduce facial dysmorphology in children with Down syndrome when taken during the first three years of life. Additional experimental research in mice confirmed the positive effects at low doses. However, they also found that high doses of the extract can disrupt facial and bone development. More research is needed to fully understand the effects of green tea extracts and therefore they should always be taken under medical supervision.
Down syndrome is caused by the presence of a third copy of chromosome 21, leading to an overexpression of the genes in this region and resulting in a number of physical and intellectual disabilities. One of the genes, DYRK1A, contributes to altering brain and bone development in people with Down syndrome. The green tea compound EGCG (epigallocatechin-3-gallate) is known to inhibit DYRK1A activity, although it also has other mechanisms of action. Previous research has shown the potential of EGCG to improve cognition in young adults with Down syndrome.
In a new study, researchers analysed the effect of green tea supplements on facial development in Down syndrome. In the experimental part of the study, the EGCG supplements were tested in mice at different dosages. In a second part of the research, they did an observational study on children with and without Down syndrome. This work, led by the Centre for Genomic Regulation (CRG), European Molecular Biology Laboratory (EMBL) and University of Barcelona in Spain and KU Leuven in Belgium, is an international effort involving researchers from University of Central Florida, La Salle — University Ramon Llull, and IMIM — Hospital del Mar Medical Research Institute.
For the mouse study, carried out at KU Leuven, the researchers started the treatment before birth, while the pups were developing in the wombs of their mothers, by adding either a low or a high dose of green tea extracts to their drinking water. “The low dose treatment had a positive effect on mice that are a model of Down syndrome,” Professor Greetje Vande Velde (KU Leuven) comments, co-lead author of the study. “Sixty percent of them showed a facial shape similar to the control group.”
“The high dose treatment, however, generated very mixed results, and even disrupted normal facial development in some cases, causing additional dysmorphology. This occurred in all mice, in the model of Down syndrome as well as in the control group.”
Age-dependent effects
The observational study was set up in Spain and also included participants from North America. 287 children between 0 and 18 years participated, including children with Down syndrome who did (n = 13) or didn’t (n = 63) receive EGCG supplementation. The treated group were all self-medicated and didn’t follow a prescribed protocol.
“All participants were photographed from various angles to create a 3D model of their faces,” explains Neus Martínez-Abadías, professor at the University of Barcelona and co-lead author of the study. “We use 21 facial landmarks, and the distances between them, to compare the faces of the participants. In the youngest group between 0 and 3 years, we observed that 57 percent of the linear distances are significantly different when you compare the faces of children with Down syndrome that never received the treatment to those of children that do not have Down syndrome. For babies and toddlers who did receive EGCG treatment, this difference was much smaller, only 25 percent. After green tea supplementation, the facial dysmorphology decreases and the children with or without Down syndrome look more alike.”
“We didn’t identify a similar effect in the adolescent group. Even when treated with green tea extracts, children with Down syndrome still show a difference of more than 50 percent compared to the control group. These findings suggest that the green tea supplements only affect facial development when they are administered in the early stages of life when the face and skull are rapidly growing.”
Further research required
“Despite the potential benefits we observed, we must handle these findings with caution considering they are preliminary and based on an observational study,” Professor Vande Velde warns. “Much more research is necessary to evaluate the effects of EGCG-containing supplements, the appropriate dose and their therapeutic potential in general. We also need to take into the account possible effects on other organs and systems, not just on the development of the face. This requires first more basic research in the lab with mice, and then clinical studies with more participants and controlled use of these supplements.”
“Our findings suggest that effects of EGCG strongly depend on the dose.” Professor Martínez-Abadías concludes. “EGCG products are commercially available and they are used regularly as a general health-promoting compounds. However, it’s important to follow the European Food Safety Authority recommendations regarding the maximal intake and to always consult a physician before taking the supplements. Our research shows potential beneficial effects of facial development at low doses, but at very high doses they can produce unpredictable effects in mice. More research is needed in humans to determine the optimal dose at each age that maximizes the potential benefits.”

Story Source:
Materials provided by KU Leuven. Note: Content may be edited for style and length.

WEHI researchers have uncovered a process cells use to fight off infection and cancer that could pave the way for precision cancer immunotherapy treatment.
Through gaining a better understanding of how this process works, researchers hope to be able to determine a way of tailoring immunotherapy to better fight cancer.
Led by Dr Dawn Lin and Dr Shalin Naik and published in Nature Cell Biology, the research provides new insight into the way cells adapt to fight infection.
This research lays the foundation for future studies into the body’s response to environmental stressors, such as injury, infection or cancer, at a single cell level.
At a glance
WEHI researchers have studied dendritic cells, a crucial component of the immune system, to gain a deeper understanding of how the body produces these cells to fight cancer and infection.
The study found how the Flt3L hormone increased dendritic cells numbers.
Researchers will now apply this knowledge to improving immunotherapy techniques to create more personalised treatments.
Flt3L hormone plays vital role in fighting off infection
Dendritic cells are immune cells that activate ‘killer’ T cells, which are vital for clearing viral infections, such as COVID-19, but also for triggering a response to cancers such as melanoma and bowel cancer.

advertisement

The Flt3L hormone can increase dendritic cell numbers, helping the immune system to fight off cancer and infection.
Dr Naik and his team studied developing immune cells at a single cell level to gain a deeper understanding of how the body uses these cells to trigger immune responses.
“There is one type of dendritic cell that the body uses to fight some infections and cancer. The Flt3L hormone increases numbers of this particular dendritic cell,” he said.
“We know quite well how the dendritic cell fights the cancer, but we don’t know how the Flt3L hormone increases the numbers of those dendritic cells.”
Single-cell barcoding provides vital clues to how dendritic cells function
Researchers used a single-cell ‘barcoding’ technique to uncover what happened when dendritic cells multiplied.

advertisement

“By using cellular barcoding — where we insert short synthetic DNA sequences, we call barcodes inside cells — we were able to determine which cells produced dendritic cells in pre-clinical models,” Dr Naik said.
“As a result of this research, we now better understand the actions of the Flt3L hormone that is currently used in cancer immunotherapy trials, and how it naturally helps the body fight cancer and infection. This is a first step to design better precision immunotherapy treatments for cancer.”
Using single cell technology to improve immunotherapy treatment
This research answers a 50-year-long question as to what causes a stem cell to react in response to immense stress, such as infection or inflammation.
“We have known that the Flt3L hormone increases the number of dendritic cells for decades but now there is a focus on applying this knowledge to cancer immunotherapy and potentially to infection immunotherapy as well,” Dr Naik said.
“The next stage in our research is to create ‘dendritic cell factories’ using our new knowledge, to produce millions to billions of these infection fighting cells and then use those in immunotherapy treatments.”
“These findings are a vital first step to improving immunotherapy treatments for patients, to help them better fight cancer and infection.”
This work was made possible with funding from the National Health and Medical Research Council, the Australia Research Council, Gilead, the Victorian Cancer Agency and the Victorian Government.

New research from UBC finds that higher life satisfaction is associated with better physical, psychological and behavioural health.
The research, published recently in The Milbank Quarterly, found that higher life satisfaction is linked to 21 positive health and well-being outcomes including:
a 26 per cent reduced risk of mortality
a 46 per cent reduced risk of depression
a 25 per cent reduced risk of physical functioning limitations
a 12 per cent reduced risk of chronic pain
a 14 per cent reduced risk of sleep problem onset
an eight per cent higher likelihood of frequent physical activity
better psychological well-being on several indicators including higher: positive affect, optimism, purpose in life, and mastery — as well as lower: hopelessness, negative affect, perceived constraints, and loneliness
Dr. Eric Kim and his team examined data from a nationally representative sample of 12,998 U.S. adults over age 50, in which participants were asked to self-evaluate their life satisfaction and health.
This study is the first to see whether a positive change in life satisfaction is associated with better outcomes on a wide range of physical, behavioural and psychosocial health and well-being indicators over a four-year period.
“Life satisfaction is a person’s evaluation of his or her own life based on factors that they deem most relevant,” says Dr. Kim, an assistant professor in UBC’s psychology department and lead author of the study. “While life satisfaction is shaped by genetics, social factors and changing life circumstances, it can also be improved on both the individual level as well as collectively on the national level.”
Dr. Kim says in recent years, intergovernmental organizations such as the United Nations (UN) and the World Health Organization have urged countries to use well-being indicators in addition to traditional economic indicators, like GDP, when making policy decisions.
“The results of this study suggest that life satisfaction is a valuable target for policymakers to consider when enhancing physical, psychological and behavioural health outcomes at the policy level,” says Dr. Kim.
The researchers decided to examine a four-year time period as there is emerging evidence that indicates changing levels of life satisfaction is an important determinant of voting behaviour. Further, election cycles happen approximately every four years in many countries.
“It is in the interest of policymakers’ election and reelection campaigns to consider how life satisfaction can be improved,” says Dr. Kim. “But more importantly understanding what the downstream health and well-being effects of altering life satisfaction might be for populations over a four-year period is critical to evaluate, and this is precisely the kind of question we tried to answer in our study.”
Dr. Kim says policy-makers who are interested in looking for practical ideas on how to improve life satisfaction at the policy level can look to the Global Happiness and Well-Being Policy Report, which is generated out of a broader UN initiative co-led by UBC economics professor emeritus Dr. John Helliwell and Columbia University professor Dr. Jeffrey Sachs.
“As our nations pause and reevaluate our priorities in light of the widespread change caused by COVID-19, our policymakers have a rare and excellent opportunity to pursue well-being for all in the post-pandemic world.”

Story Source:
Materials provided by University of British Columbia. Note: Content may be edited for style and length.

Neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease are in the firing line after researchers identified an attractive therapeutic drug target.
An international collaboration, co-led by University of Queensland researchers, has isolated and analysed the structure and function of a protein found in the brain’s nerve fibres called SARM1.
Dr Jeff Nanson said the protein was activated when nerve fibres were damaged by injury, disease, or as a side effect of certain drugs.
“After a damaging incident occurs, this protein often induces a form of nerve fibre degeneration — known as axon degeneration — a ‘self-destruct’ mechanism of sorts,” Dr Nanson said.
“This is a key pathological feature of many terrible neurodegenerative diseases, such as Parkinson’s and Alzheimer’s disease, and also amyotrophic lateral sclerosis (ALS), traumatic brain injury, and glaucoma.
“There are currently no treatments to prevent this nerve fibre degeneration, but now we know that SARM1 is triggering a cascade of degeneration we can develop future drugs to precisely target this protein.

advertisement

“This work will hopefully help design new inhibiting drugs that could stop this process in its tracks.”
Professor Bostjan Kobe said the researchers analysed the structure of the protein and defined its three-dimensional shape using X-ray crystallography and cryo-electron microscopy.
“With X-ray crystallography, we make proteins grow into crystals, and then shoot X-rays at the crystals to get diffraction,” Professor Kobe said.
“And with cryo-electron microscopy, we freeze small layers of solution and then visualise protein particles by a beam of electrons.
“The resulting 3D images of SARM1’s ring-like structure were simply beautiful, and truly allowed us to investigate its purpose and function.

advertisement

“This visualisation was a highly collaborative effort, working closely with our partners at Griffith University and our industry partners.”
The researchers hope that the discovery is the start of a revolution in treatments for neurodegenerative disorders.
“It’s time we had effective treatments for these devastating disorders,” Dr Nanson said.
“We know that these types of diseases are strongly related to age, so in the context of an ageing population here in Australia and globally, these diseases are likely to increase.
“It’s incredibly important that we understand how they work and develop effective treatments.”
The study was led by researchers at UQ, Griffith University, Washington University (St Louis), and industry partner Disarm Therapeutics.

Story Source:
Materials provided by University of Queensland. Note: Content may be edited for style and length.

Ask Eric Weaver about pandemics, and he’s quick to remind you of a fact that illustrates the fleeting nature of human memory and the proximal nature of human attention: The first pandemic of the 21st century struck not in 2019, but 2009.
That’s when the H1N1/09 swine flu emerged, eventually infecting upwards of 1.4 billion people — nearly one of every five on the planet at the time. True to the name, swine flus jump to humans from pigs. It’s a phenomenon that has been documented more than 400 times since the mid-2000s in the United States alone.
“They’re considered the great mixing vessel,” said Weaver, associate professor of biological sciences at the University of Nebraska-Lincoln. “They’re susceptible to their own circulating influenzas, as well as many of the avian and human influenzas.
“If you put an avian, a swine and a human virus into the same cell, they can swap genome segments. When you mix those viruses in the swine, what pops out could be all swine, or a little human and swine, or a little avian and swine, or a little of all three. And you never know: You might get the perfect combination of parts that makes for a very high-fitness virus that is highly transmissible and new to humans, meaning that people don’t have immunity to it.”
All of it helps explain why Weaver has spent years researching how to develop a vaccine that protects against as many strains of influenza as possible, including those that have yet to emerge. In a new study, Weaver, doctoral candidate Brianna Bullard and colleagues have debuted the results of an approach that demonstrates promising signs of protection against more than a dozen swine flu strains — and more than a leading, commercially available vaccine.
“This is the best data I’ve ever seen in the (research) literature,” Weaver said of the team’s findings, recently published in the journal Nature Communications.

advertisement

The “H” and “N” in H1N1 refer to two crucial proteins, hemagglutinin and neuraminidase, that reside on the surface of influenza viruses and allow them to enter and exit cells. But it’s the H3 subtype of influenza — H3N2, specifically — that has accounted for more than 90% of swine-to-human infections in the United States since 2010, making it the target of Weaver’s most recent research.
In his efforts to combat multiple strains of swine H3N2, Weaver employed a computational program, Epigraph, that was co-developed by Bette Korber of Los Alamos National Laboratory. The “epi” is short for epitope: the bit of a viral protein, such as hemagglutinin, that draws the attention of an immune system. Any one epitope, if administered as a vaccine, will stimulate an immune response against only a limited number of closely related viral strains.
So Weaver put Epigraph to work analyzing data on every known and available mutational variant of hemagglutinin, which it then used to predict which collection of epitopes would grant immunity against the broadest, most diverse range of strains. Those hemagglutinin proteins are usually composed of around 560 amino acids, whose type and sequence determine the structure and function of the epitopes. Starting at the start of an amino acid string, Epigraph analyzed the sequence of amino acids No. 1 through No. 9 before sliding down to analyze Nos. 2-10, then 3-11, and so on. After doing the same for every epitope, the program determined the most common nine-acid sequences from the entire batch — the entire catalogue of known H3N2 strains in pigs.
“So what you end up with are the most common epitopes that exist in nature linked together, then the second-most common, and then the third-most common,” Weaver said. “When you look at it from an evolutionary standpoint, the first resembles what most of the viruses look like. The second starts to look a bit different, and the third looks even more different.
“But all three of these make a contribution to the vaccine itself, and they work through slightly different mechanisms.”
When testing the resulting three-epitope cocktail in mice and pigs, the team found that it yielded immune response signatures and physiological protection against a much wider variety of strains than did FluSure, a commercial swine vaccine.

advertisement

In mice, the team tested its vaccine against 20 strains of swine-derived H3 flu. The vaccine generated clinically relevant concentrations of antibodies — the molecules that neutralize a virus before it enters a cell — against 14 of those 20 strains. FluSure managed the same feat against just four of the 20. A separate experiment presented the mice with four strains that represented a cross-section of H3 diversity. In all four cases, Epigraph-vaccinated mice produced notable levels of T-cells, which, among other responsibilities, instruct infected cells to die for the sake of avoiding further viral transmission. FluSure-vaccinated mice, by contrast, showed little T-cell response to any of the four strains.
Those cellular-level responses appeared to scale up, too. When challenged with flu viruses, Epigraph-vaccinated mice generally lost less weight, and exhibited fewer viral particles in the lungs, than did their FluSure-vaccinated counterparts. And when mice were challenged with a lethal H3 strain derived from humans, only the Epigraph vaccine protected all of the specimens that received it.
That performance carried over to pigs. Cells taken from swine injected with just one dose of the Epigraph vaccine produced substantial antibodies in response to 13 of 20 H3 strains, including 15 of 16 that originated in North America or were derived from humans. A single dose of FluSure, meanwhile, generated significant antibodies against none of the 20. Though a second dose of FluSure did elevate those antibody concentrations, they remained about four times lower, on average, than the Epigraph-induced responses. T-cell responses, too, remained higher in Epigraph-vaccinated pigs.
More, and more-generalizable, experiments will be needed to verify the Epigraph vaccine’s performance, Weaver said. For one, the team is looking to test whether the vaccine candidate generates actual immunity in living pigs, beyond the promising immune responses from their cells in a lab. There’s also the matter of determining how long any immunity might last.
But Weaver has already developed a human equivalent of the swine flu vaccine cocktail that he’s likewise preparing to test. Considering the similarities between flu infections in humans and pigs — susceptibilities to subtypes, clinical symptoms, even viral receptors in respiratory tracts — he said the recent findings bode well for those future, human-centric efforts. Success on that front could eventually mean pivoting away from the current approach to flu vaccinations, whereby virologists are forced to predict which strains will dominate a flu season — and, despite their best efforts, sometimes miss the mark.
“This study is equivalent to a bench-to-bedside study, where the positive results in the preclinical mouse study are confirmed by positive results in a clinical pig study,” Weaver said. “This gives us confidence that when the concept is applied to human influenza virus, we’ll see the same translation from preclinical studies to clinical studies in humans.”
Weaver, Bullard and Korber authored the Nature Communications study with Brigette Corder, doctoral student at Nebraska, along with Richard Webby, Jennifer DeBeauchamp and Adam Rubrum of St. Jude Children’s Research Hospital. The team received support from the National Institutes of Health.

Wine lovers recognize that a perfectly paired wine can make a delicious meal taste even better, but the reverse is also true: Certain foods can influence the flavors of wines. Now, researchers reporting in ACS’ Journal of Agricultural and Food Chemistry have explored how lipids — fatty molecules abundant in cheese, meats, vegetable oils and other foods — interact with grape tannins, masking the undesirable flavors of the wine compounds.
Tannins are polyphenolic compounds responsible for the bitterness and astringency of red wines. Wine testers have noticed that certain foods reduce these sensations, improving the flavor of a wine, but scientists aren’t sure why. Some studies have indicated that tannins interact with lipids at the molecular level. In foods, lipids are found as fat globules dispersed in liquids or solids. Julie Géan and colleagues wanted to investigate how tannins influence the size and stability of lipid droplets in an emulsion. They also wondered how the prior consumption of vegetable oils would impact the taste of tannins for human volunteers.
The researchers made an oil-in-water emulsion using olive oil, water and a phospholipid emulsifier. Then, they added a grape tannin, called catechin, and studied the lipids in the emulsion with various biophysical techniques. The team found that the tannin inserted into the layer of emulsifier that surrounded the oil droplets, causing larger droplets to form. In taste tests, volunteers indicated that consuming a spoonful of rapeseed, grapeseed or olive oil before tasting a tannin solution reduced the astringency of the compounds. Olive oil had the greatest effect, causing the tannins to be perceived as fruity instead of astringent. Combining the biophysical and sensory results, the researchers concluded that tannins can interact with oil droplets in the mouth, making them less available to bind to saliva proteins and cause astringency.

Story Source:
Materials provided by American Chemical Society. Note: Content may be edited for style and length.

Researchers from the Icahn School of Medicine at Mount Sinai have identified a drug that works against depression by a completely different mechanism than existing treatments.
Their study showed that ezogabine (also known as retigabine), a drug that opens KCNQ2/3 type of potassium channels in the brain, is associated with significant improvements in depressive symptoms and anhedonia in patients with depression. Anhedonia is the reduced ability to experience pleasure or lack of reactivity to pleasurable stimuli; it is a core symptom of depression and associated with worse outcomes, poor response to antidepressant medication, and increased risk of suicide.
Ezogabine was approved by the U.S. Food and Drug Administration in 2011 as an anticonvulsant for epilepsy treatment but had not been previously studied in depression. The research results, published March 3 in the American Journal of Psychiatry, provide initial evidence in humans for the KCNQ2/3 channel as a new target for novel drug discovery for depression and anhedonia.
“Our study is the first randomized, placebo-controlled trial to show that a drug affecting this type of ion channel in the brain can improve depression and anhedonia in patients. Targeting this channel represents a completely different mechanism of action than any currently available antidepressant treatment,” says James Murrough, MD, PhD, Associate Professor of Psychiatry, and Neuroscience, Director of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai, and senior author of the paper.
The new drug target, the KCNQ2/3 channel, is a member of a large family of ion channels referred to as the KCNQ (or Kv7) family that act as important controllers of brain cell excitability and function in the central nervous system. These channels affect brain cell function by controlling the flow of the electrical charge across the cell membrane in the form of potassium (K+) ions. Researchers at Mount Sinai, including study co-author Ming-Hu Han, PhD, Professor of Pharmacological Sciences, and Neuroscience, had previously conducted a series of studies in mice showing that changes in the KCNQ2/3 potassium channel play an important role in determining if the animals show depression and anhedonic-like behavior following chronic stress in an experimental model of depression. In particular, mice that appear to be resistant to developing depression in the face of stress show an increase in KCNQ2/3 channels in the brain.
“We viewed enhanced functioning of the KCNQ channel as a potential molecular mechanism of resilience to stress and depression,” said Dr. Han, who also discovered that if he gave a drug that could increase the activity of this channel, such as ezogabine, to mice that had become depressed in the stress model, the mice no longer showed the depression and anhedonic behaviors; in other words, the drug acted as an antidepressant.
The current study was a two-site, double-blind, randomized, placebo-controlled proof of concept clinical trial designed as a preliminary test of the hypothesis that increasing KCNQ2/3 channel activity in the brain is a viable new approach for the treatment of depression. Forty-five adult patients diagnosed with a depressive disorder were assigned to a five-week treatment period with daily dosing of either ezogabine or matching placebo. All participants underwent clinical evaluations and functional magnetic resonance imaging (fMRI) during a reward task at baseline and at the end of the treatment period. Compared to patients treated with placebo, those treated with ezogabine showed a significant and large reduction in several key measures of depression severity, anhedonia, and overall illness severity. For example, significant improvements following treatment with ezogabine compared to placebo was observed using the Montgomery-Asberg Depression Rating Scale (MADRS), the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), the Snaith-Hamilton Pleasure Scale (SHAPS), and the Temporal Experience of Pleasure Scale (TEPS)-Anticipatory Subscale. The ezogabine group showed also a trend towards an increase in response to reward anticipation in the brain compared to placebo although this effect did not reach statistical significance.
“The fundamental insight by Dr. Han’s group that a drug that essentially mimicked a mechanism of stress resilience in the brain could represent a whole new approach to the treatment of depression was very exciting to us,” said Dr. Murrough.
In collaboration with Dr. Han, Dr. Murrough carried out a series of studies in patients with depression to begin to test if the observations in mice could be translated to humans. An initial open-label (no placebo) study in patients with depression led by Dr. Murrough provided initial evidence that ezogabine could improve symptoms of depression and anhedonia in a manner that was associated with changes in brain function.
“I think it’s fair to say that most of us on the study team were quite surprised at the large size of the beneficial effect of ezogabine on clinical symptoms across multiple measures related to depression. We are greatly encouraged by these findings and the hope they offer for the prospect of developing novel, effective treatments for depression and related disorders. New treatments are urgently needed given that more than one-third of people suffering from depression are inadequately treated with currently approved therapeutics.”
This research was supported by the National Institute of Mental Health. Additional funding was provided by the Friedman Brain Institute at the Icahn School of Medicine at Mount Sinai and the Ehrenkranz Laboratory for Human Resilience, a component of the Depression and Anxiety Center for Discovery and Treatment at the Icahn School of Medicine at Mount Sinai.
Study authors James Murrough, MD, PhD and Ming-Hu-Han, PhD, are named inventors on a pending patent application for the use of ezogabine and other KCNQ channel openers to treat depression and related disorders.