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To monitor heart rhythms and muscle function, doctors often attach electrodes to a patient’s skin, detecting the electrical signals that lie beneath. These impulses are vital to the early diagnosis and treatment of many disorders, but currently available electrodes have limited function or are expensive to manufacture. Researchers reporting in ACS Nano, however, have now developed a low-cost, spongy version with improved signal detection that’s made with a surprising template — a sugar cube.
The current gold-standard electrodes for electrophysiologic monitoring rely on a silver disc that contacts the skin through a conductive gel. These electrodes are critical tools for detecting abnormal electrical signals linked to health issues, such as heart attacks, brain disorders or neuromuscular diseases. These devices are not without their drawbacks, however. They are rigid and cannot conform well to the skin, particularly when the patient is physically active, reducing signal quality. In addition, the conductive gel dries quickly, preventing long-term monitoring and rare-event detection. Addressing these challenges, researchers have designed soft electrodes that better conform to the skin, as well as microneedle-based versions that physically penetrate the skin, but these are expensive to manufacture, limiting their widespread use. So, Chuan Wang and colleagues wanted to develop a low-cost sponge-like electrode that would offer more consistent and resilient skin contact.
To make the new device, researchers started with commercially available sugar cubes, which they molded into a template that was dipped into liquid polydimethylsiloxane (PDMS). The PDMS became a solid structure after a curing step. They then dissolved the sugar with hot water and coated the sponge’s micropores with a conductive thin film to form the electrode.
Because the micropores allowed the spongy material to have increased contact area with the skin, the new device showed strong signal intensity and reduced noise when compared with standard electrodes. The micropores also helped the device carry more conductive gel, which kept them from drying out as quickly and losing signal, compared to standard versions. The gel also acted as a shock absorber, reducing the negative impacts of patient movement on skin-electrode contact and ensuring signal detection. The researchers tested the ability of the sponge device to monitor uterine contractions during labor and found it performed as well as, or better than, a conventional electrode. As a low-cost, flexible alternative, sponge electrodes expand the possibilities for wearable health care applications, including use in medical exams that require patients to move, or for long-term monitoring of people at home or at work, say the researchers.
The authors acknowledge funding from the Bill & Melinda Gates Foundation.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

From the wide variety of sodas, candies and baked goods that are sold worldwide, it’s clear that people love their sweet treats. But consuming too much white table sugar or artificial sweetener can lead to health issues. In the search for a better sweetener, researchers in ACS’ Journal of Agricultural and Food Chemistry now report a low-calorie mixture that is as sweet as table sugar and, in lab experiments, feeds “good” gut microbes.
Artificial sweeteners have exploded in popularity because they let people consume sweets without the calories. However, while they’re considered safe for human consumption, studies in animals and humans suggest that some of them can stimulate appetite, leading to increased food consumption and weight gain, as well as other negative health outcomes. So, researchers have been turning to the study of low-calorie or extremely sweet substances from natural sources as possible replacements. For example, galactooligosaccharides — found in mammalian milk — are low-calorie sugars with prebiotic activity that can be a source of energy for beneficial gut microbes, but they’re not quite sweet enough to replace table sugar. Alternatively, extracts from the luo han guo fruit contain mogrosides — compounds 200 to 300 times sweeter than table sugar. But these extracts sometimes have off-flavors, which can be removed with enzymes. So, F. Javier Moreno and colleagues wanted to take advantage of the best aspects of both natural substances, using enzymes to modify mogrosides while simultaneously producing galactooligosaccharides for a brand-new low-calorie sweetener.
The researchers started with lactose and mogroside V (the primary mogrosidein luo han guo fruit). When they added β-galactosidase enzymes, the researchers obtained a mixture that contained mostly galactooligosaccharides and a small amount of modified mogrosides. A trained sensory panel reported that the new combination had a sweetness similar to that of sucrose (table sugar), suggesting it could be acceptable to consumers. In test tube experiments, the new sweetener increased the levels of multiple human gut microbes that are beneficial, including Bifidobacterium and Lactobacillus bacterial species. In addition, increases in bacteria-produced metabolites, such as acetate, propionate and butyrate, indicated that the mixture could potentially have a prebiotic effect on the gut microbiome. The researchers say that the new sweetener holds promise in these initial analyses, and their next step is to more closely study the substance’s impact on human gut health.
The authors acknowledge funding from Optibiotix Health Plc (York, U.K.), the Spanish Ministry of Science, Innovation and Universities, and the European Union’s Horizon 2020 research and innovation program. One of the study’s authors is employed by Optibiotix Health Plc.
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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

A study of how injured mouse cells trigger immune responses suggests novel strategies for preventing and treating everything from parasites to allergies in humans.
Researchers hypothesized that gut cells damaged by parasitic worms summon the immune system by releasing adenosine triphosphate (ATP), which is metabolized into the nucleotide adenosine. Adenosine, in turn, binds to specific receptors on the surface of intestinal epithelial cells to trigger an immune response.
Members of the research team — who hail primarily from Rutgers and Columbia, but also include investigators from Harvard, the University of Texas-Houston and the University of Ferrara — tested their theory by injecting worms into mice engineered to lack adenosine receptors on their epithelial cells. Unlike regular mice, which mount a robust immune response to these parasites, the specially engineered mice mounted a markedly reduced immune response.
Parasitic worms known as helminths infect about 1.5 billion people, according to the study. A vaccine isn’t available, but this discovery about how the body naturally defends itself against helminths opens an avenue for development.
“If you combined a protein that’s unique to helminths with an agonist that could trigger the adenosine receptor, you might be able to create a vaccine that would sensitize the immune system,” said senior author William Gause, the director of the Rutgers Institute for Infectious and Inflammatory Diseases (i3D), who is at Rutgers New Jersey Medical School. When actual infection occurred, the memory immune response would be faster and stronger.”
“On the other side, this finding suggests that it may be possible to treat allergies, which are basically unwanted immune responses, with medications that block adenosine receptors and reduce the immune response and associated harmful inflammation,” Gause said.
So-called danger signals released by injured cells are one of the two main ways the immune system learns of attackers. These signals are less understood than the other immune system trigger, molecules released by pathogens that are recognized by specific receptors on immune cells.
Gause said release of ATP may prove to be a common and important danger signal for injured cells. Every cell in the body contains ATP that can release when injured.
The researchers plan a follow-up study that will explore whether lung cells use the same signal to alert the immune system of invaders.
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Materials provided by Rutgers University. Original written by Andrew Smith. Note: Content may be edited for style and length.

The pandemic has called attention to an issue that nursing home residents, their families and those who work in nursing homes have been aware of for a long time. Recruiting and retaining both the nursing home staff who provide the very personal care needed by residents and the administrators who set the tone of the workplace are key challenges in nursing homes.
Regenstrief Institute and Indiana University School of Medicine researcher-clinicians, Jennifer L. Carnahan, M.D., MPH, and Kathleen Unroe, M.D., MHA, add that continuity of nursing home staff and of leadership is linked to improving quality of resident care — from onsite treatment or post-hospital care for complex medical issues to assistance with basic care needs such as eating and bathing. Their editorial, “Prioritizing nursing home staff and leadership consistency to improve quality,” is published in Journal of the American Geriatrics Society (JAGS).
An ongoing trust relationship with nursing home staff enables residents to feel comfortable with the very personal care they require and enables the hardworking caregiver to know and interact skillfully with residents as individuals rather than focusing just on tasks.
Staff turnover affects the family as well as residents. Family members rely on those providing care to their loved ones to keep them apprised of changes that typically only someone in close regular contact with the nursing home resident might observe. These might be subtle mood changes, loss of interest in previously enjoyed activities or inability to perform a task with which they had not previously had a problem.
“Doctors and nurses are obviously important, but it should be recognized that frontline nursing home staff deliver 90 percent of care and thus are critical to creating a high-quality long-term care system,” said Dr. Unroe. “Everyone agrees we have a recruitment and retention problem. We need to devise incentives to attract and keep people in this workforce who enjoy working with older adults, and are well trained, especially in the needs of people with dementia.”
Dr. Unroe, a geriatrician, and a past chair of the American Geriatrics Society Public Policy Committee, currently serves as a member of the technical expert panel of the Centers for the Medicare & Medicaid Services (CMS) Five-Star Quality Rating System. The online tool provides more than 100 quality metrics divided into five categories: mortality, safety of care, readmission to hospitals, patient experience and timely and effective care. These measurements enable older adults, their families, social services and others to evaluate and compare quality of care provided to residents.
“We need to prioritize nurturing and supporting staff so that they can deliver the hands-on care nursing home residents require,” said editorial co-author Dr. Carnahan. “Given the importance of continuity to quality of care for this vulnerable population and the current lack of viable solutions to improve staff and leadership recruitment and retention, researchers, in partnership with nursing home operators, must take the lead in developing and testing practical and reproduceable strategies to attract and keep a talented workforce and leadership.”
Dr. Carnahan, a geriatrician, is a current Leadership in Health Policy scholar with the Society of General Internal Medicine and serves on the society’s Geriatrics Commission.
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Materials provided by Regenstrief Institute. Note: Content may be edited for style and length.

Investigators from Cedars-Sinai Cancer have identified genetic signatures that could predict whether tumors in patients with bladder and other cancers will respond to immunotherapy. Their results, published today in the peer-reviewed Journal of the National Cancer Institute, could one day help guide clinicians to the most effective treatments for cancer patients.
“Our work indicates that these genetic signatures may prove to be tremendously valuable in predicting immunotherapy response in patients with bladder cancer, but also other tumor types,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer, the PHASE ONE Foundation Distinguished Chair and senior author of the study. “We will continue investigating these biomarkers with the goal of bringing them into clinical use and improving patient outcomes.”
During the past five years, anti-PD-1/PD-L1 therapy — a type of cancer immunotherapy that paves the way for the body’s immune system to attack tumor cells — has proved effective against many cancer types, according to Keith Syson Chan, PhD, a translational scientist, professor of Pathology and co-author of the study.
“It has proven very effective against melanoma and revolutionized lung cancer treatment,” Chan said. “Bladder cancer is considered one of the more responsive tumor types, but still has just a 25% durable response rate, so improvement is still needed.”
When a tumor causes a host immune reaction, immune cells usually are able to infiltrate the core of the tumor, and scientists call it a “hot” tumor. Some tumors, on the other hand, block immune cells from infiltrating and are known as “cold” tumors.
A previous study by Theodorescu implicated a gene — called discoidin domain receptor tyrosine kinase 2 (DDR2) — in contributing to anti-PD-1 resistance in animal models in several tumor types. In a collaboration between cancer biologists and bioinformatics researchers, this new study further investigated the DDR gene family using human cancer data sets in various tumor types.

Scientists have long tried to introduce genetically engineered bacteria into the gut to treat diseases. In the past, these attempts have focused on engineering common lab strains of E. coli, which cannot compete with the native gut bacteria that are well adapted to their host. Now, a group of researchers from the University of California, San Diego, successfully engineered E. coli collected from both human and mice gut microbiomes and showed that they have the potential to treat diseases such as diabetes. Their finds are publishing in the journal Cell on August 4.
“All I can say to the non-native bacteria is good luck. The gut microbiome is very dynamic and is constantly changing, making things even harder for the non-native bacteria,” says Amir Zarrinpar, a gastroenterologist at UC San Diego Health and the senior researcher of the paper. “It is challenging for bacteria that have never lived inside of a mammal before to now go into the gut microbiome jungle with all of these hostile conditions that are geared towards preventing bacterial invaders from taking hold.”
The group devised a solution to this problem by directly engineering E. coli collected from the hosts. “Bacteria in our body are adapted to each one of us specifically: the kind of foods we eat, the common stresses our body experiences or induces, and our genetic background,” says Zarrinpar. “This constantly fluctuating environment is their normal.” This is a big advantage for native bacteria and makes them ideal candidates for engineering.
“We have engineered these bacteria to become factories that can live in our microbiome and potentially produce medicines,” says Zarrinpar. “We know that E. coli can pick up pathogenic genes and cause disease, and now we’re just realizing that if we put a beneficial gene in, it can help us to treat chronic diseases, maybe even cure some of them.”
The team first collected stool samples from the host and extracted E. coli for further modifications. “We say to the bacteria: Hey, we will give you a new superpower, which you may not even benefit from, but we will put you right back into the environment that you thrive in,” says Zarrinpar.
The superpower that the team gave to these specific bacteria is a protein called bile salt hydrolase (BSH). After a single treatment in mice, E. coli with BSH were found throughout the entire gut of the mice and they retained their BSH activity for the entire lifetime of the host. The group also show that the BSH activity was able to positively influence diabetes progression in mice.
This is a significant improvement over similar treatments with non-native laboratory strains of engineered bacteria, where more than one treatment is often required. And these engineered bacteria do not stay in the host’s gut for nearly as long as, or as consistently as, the native E. coli method identified by Professor Zarrinpar’s team.
In addition to successfully influencing diabetes in mice, the group was also able to make a similar modification to E. coli extracted from human gut.
While they have demonstrated substantial results, engineering native bacteria comes with another set of challenges. “Native bacteria are very resistant to modifications; it is part of their innate defense mechanism,” says Zarrinpar. Their data suggest that inserting a gene into a native bacterium has about 100-fold lower success rate than doing so with lab strain bacteria, but Zarrinpar and his team are optimizing this process. “There are many new genetic engineering tools available now that will allow us to engineer these bacteria more effectively,” says Zarrinpar.
The group is planning on using this technology to find ways to treat more diseases. “We are dreaming big,” says Zarrinpar. “This technology is something that can potentially open up the application of the microbiome therapy to influence so many different chronic and genetic diseases.”
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Materials provided by Cell Press. Note: Content may be edited for style and length.

For the first time, scientists have designed a phage combination therapy that can precisely target and suppress gut bacteria associated with inflammatory bowel diseases (IBD). Presented on August 4 in the journal Cell, the work showcases the possibility of using phages for treating diseases associated with gut microbiota.
“The biggest problem with applying phage therapies is that there is a constant arms race between bacteria and phages,” says Eran Elinav, director of the Systems Immunology department, Weizmann Institute of Science and the Microbiome & Cancer Division, German National Cancer Center (DKFZ) and the corresponding author of the study. “If you apply a single phage on a bacterium, the bacterium would likely develop resistance mechanisms very rapidly. To our knowledge, we are the first to use an orally-administered phage combination therapy against a disease-contributing gut commensal, while tackling the huge issue of phage resistance and treating a non-communicable disease.”
IBD includes a group of chronic inflammatory disorders of the gut that affect millions of people in the world. While the cause of IBD remains unclear, previous research has suggested that certain bacteria in the gut are linked to the disease. Researchers have tried using antibiotics to treat IBD, but these therapies are not sufficiently specific or effective. Antibiotics kill the friendly gut bacteria along with the pathogenic ones, can cause adverse effects, and give rise to antibiotic-resistant bacteria.
“This proof-of-concept study utilizes phages as a precision weapon in suppressing a group of commensal strains contributing to IBD,” says Elinav. “But our vision is that this new modality could potentially be developed and applied against a number of other IBD-associated bugs, and also against commensals that are involved with other diseases, including obesity, diabetes, cancer, neurodegenerative diseases, and more.”
Elinav’s team, in collaboration with a group of international scientists, and the Weizmann Institute of Science’s spinoff phage therapy company BiomX Ltd compared the gut microbiota compositions of 537 IBD patients to healthy controls enrolled in cohort studies in France, Israel, the U.S., and Germany. The team found IBD patients, despite their differences in geography, ethnicity and diet, tend to have a group of Klebsiella pneumoniae (Kp) strains enriched in their gut, especially in those who are experiencing disease flare-ups. When transplanting the Kp into mice, the team found that mice developed a severe intestinal inflammation and tissue damage, suggesting that these Kp strains may contribute to worsening of IBD.
Next, Elinav and his team scanned and isolated thousands of bacteriophages from environmental samples. Bacteriophages are viruses that can target and infect bacteria. They identified some 40 phages that appear to be effective against the IBD-contributing Kp strains, including strains that have already developed phage resistance.
The team tested the phages in various groups as a potential cocktail treatment against IBD-contributing Kp strains. In these phage combinations, each of the phages uses a different receptor to enter bacteria, and kills them through different mechanisms. Even if the bacteria mutate, rendering one of their receptors resistant, there will be back-ups, Elinav says. An effective cocktail design can prevent phage-resistant bacteria from forming and spreading, he adds.
Elinav and his team discovered the most effective phage combination, which contains five phages, in suppressing the Kp strains in the test tube, as well as in mice IBD models, where the phage cocktail attenuated inflammation and tissue damage.
The team further tested two representative phages from this cocktail in a phase I clinical trial that involves 18 healthy volunteers. The experiment showed that the phages can survive at high levels and remain active throughout the gastrointestinal tract when taken with antacids while not impacting the surrounding microbiota. Participants had no severe treatment-related adverse events. The team plans to further test the 5-phage cocktail in a subsequent phase II trial encompassing IBD patients that harbor the disease-contributing Kp strains. In addition, Elinav and his team are working to identify bacteria associated with other diseases and to develop effective phage combination therapies against them.
“What we envision is a precision medical pipeline,” says Elinav. “Using it, we can characterize the pathogenic bacteria of a person suffering from a disease related to the gut microbiota, and then apply a phage therapy that would be tailored to the individual to suppress the bacteria.”
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Imperial researchers have built a new easy-to-use test that could diagnose non-infectious diseases like heart attacks and cancers more quickly.
The new test works by detecting molecular signals in the body called biomarkers, which are already used in things like COVID-19 testing where the presence of SARS-CoV-2 genes indicates COVID-19. There are also biomarkers for non-infectious diseases: for example, prostate specific antigen (PSA) in the blood can sometimes act as a biomarker to indicate the presence of prostate cancer.
Diagnostic tests based on RNA or DNA often require controlled temperatures and involve multiple steps. The new test can be used at room temperature in a user-friendly process.
The researchers hope this could enable quicker and easier diagnostics in settings like GP surgeries, as well as in resource-limited clinics in developing countries.
The new test, called CrisprZyme, has been developed by a team of researchers led by Imperial College London, MIT, and Max Delbrück Center for Molecular Medicine in Berlin. They say the test could boost access to biomarker diagnostics. The results of preliminary lab studies of the test are published today in Nature Nanotechnology.
First author Dr Marta Broto, of Imperial’s Department of Materials, said: “As well as potentially boosting access to diagnostics in developing countries, this technology could bring us a step closer to personalised diagnostics at home or at the GP surgery. By making clinical diagnostic tests simpler, we will be able to provide clinicians with the right tools to test at the same GP surgery instead of having to reschedule for follow-up analyses and blood tests.”
CRISPR-inspired

Every year, almost 7 million potentially serious bacterial infections are estimated to occur in newborns, resulting in more than 550,000 annual neonatal deaths. Most of these infections and deaths happen in LMICs, where often scarce resources can limit the capacity to diagnose and treat sepsis. These problems are further complicated by the global rise of antimicrobial resistance (AMR), particularly the rapid spread of gram-negative bacteria that are resistant to antibiotics — including Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae that are no longer susceptible to ß-lactam antibiotics, such as ampicillin and ceftazidime. AMR is already estimated to account for approximately 5 million deaths a year worldwide, and has been predicted to result in 10 million annual deaths by 2050.
Despite neonatal sepsis representing such a major health problem in LMICs, it is still unclear how, when, and where newborn babies acquire life-threatening infections. Furthermore, the factors associated with the presence of AMR in these cases are also still being elucidated. For example, there have been no studies in LMICs examining whether the presence of antibiotic-resistant bacteria in mothers is linked to the development of sepsis in their newborns.
In a new study published in Nature Microbiology, Dr. Maria Carvalho, Dr. Kirsty Sands and a network of international colleagues decided to look at the presence of antibiotic resistance genes (ARGs) in the gut microbiota — the collection of microbes that are present in the human gut — of mothers and their babies from 7 LMICs in Africa and South Asia. As part of the “Burden of Antibiotic Resistance in Neonates from Developing Societies” study, or BARNARDS — a network of 12 clinical sites across Bangladesh, Ethiopia, India, Nigeria, Pakistan, Rwanda and South Africa — they recruited 35,040 mothers and 36,285 neonates. From these, they collected 18,148 rectal swabs (15,217 from mothers and 2,931 from neonates, including 626 with sepsis), which were used to grow the bacteria present in these samples and assess the presence of clinically important ARGs in the microbiota of mothers and their babies. The authors found that a large number of samples carried genes linked to antibiotic resistance, suggesting that AMR is far more widespread in these settings than previously anticipated. For example, samples from around 1 in 5 neonates (18.5%) were positive for blaNDM, a gene that encodes New Delhi metallo-beta-lactamase, which is an enzyme that can destroy ß-lactam antibiotics including the commonly used carbapenems, resulting in the bacteria being resistant against this drug. Importantly, the researchers found that ARGs were present in neonates within hours of birth, indicating that initial colonisation of the newborns with antibiotic-resistant bacteria occurred at birth or soon after, likely through contact with the mother or from the hospital environment.
The samples collected from mothers and neonates were also used to identify the bacteria resistant to antibiotics. In total, the authors isolated 1,072 gram-negative bacteria, with the majority of these being K. pneumoniae, E. coli and E. cloacae. Whole genome sequencing revealed that while these bacteria are quite diverse across different locations, there are clear clusters associated with specific countries and hospitals. The BARNARDS team identified some cases in which bacterial isolates were shared by different neonates attending the same clinical site, suggesting that in some cases transmission of resistant bacteria from the hospital environment or between newborns may have occurred. Furthermore, the genomic analyses showed that some E. coli isolates were indistinguishable between mothers and newborns, supporting that mother-to-child transmission may occur during or after labour.
Finally, the researchers identified risk factors associated with the carriage of ARGs, looking at features associated with water, sanitation, and hygiene (WASH) and prior infections. The team found that frequent handwashing by mothers reduced the risk of carrying resistance genes (compared to occasional handwashing), whereas this risk was increased if mothers had reported an infection or taken antibiotics in the 3 months prior to being enrolled in the study. The carriage of such ARGs by mothers was also associated with an increased risk of adverse birth outcomes and neonatal sepsis.
These findings demonstrate the high prevalence of antibiotic resistance in the microbiota of mothers and their neonates in LMICs, including within hours after birth. Furthermore, the study highlights that better understanding the routes of ARG transmission, including mother-to-child and within the clinical environment, is essential to prevent neonatal sepsis. Finally, the results reinforce the importance of access to safe water, sanitation, and good hygiene to reduce AMR and lower neonatal sepsis and mortality rates in LMICs.
Professor Tim Walsh, who supervised the study, stressed the novelty of the findings: “This article demonstrates two novel observations. The first is that the incidence of AMR carriage, including carbapenem resistance, is extremely worrying, not only in South Asia but also in some parts of Africa. The second is that the incidence of carbapenem resistance is really high in newborn babies, demonstrating that AMR carriage occurs within a few days of life. Clearly, this research poses many questions about transmission and also about how the acquisition of these drug-resistant strains might impact on the growth of the baby — questions we are currently working to address within the IOI and with our collaborators.”
Dr. Kirsty Sands, who co-led the study, highlighted how the study starts to elucidate the factors governing the spread of AMR: “The BARNARDS group worked together for over seven years to produce one of the largest studies that analyses gut bacteria of women and their neonates. This study shows that transmission dynamics can be very complex, as we found links between carriage, infection, and sanitation and hygiene. We need to continue our research to fully understand these transmission dynamics, which could help to guide better infection prevention and control measures.”
As explained by Dr. Maria Carvalho, who co-led the research, the study also promoted capacity building in local sites: “BARNARDS developed and implemented a standardised methodology to attain the common objective of minimising the impact of morbidity and mortality in neonates from African and South Asian countries. We also looked at the specific needs for each site. For example, BARNARDS set up an additional maternity ward (20 beds) and a Microbiology Lab in the Murtala Muhammad Specialist Hospital Kano, Nigeria. Capacity building throughout the network at different levels (clinical, research and outreach) was a big achievement of BARNARDS.”
Dr. Rabaab Zahra, who led the study in Islamabad, Pakistan, stressed the importance of these findings for understanding and controlling the spread of AMR: “Based on our knowledge of AMR prevalence, we had speculated certain levels of resistance in neonates but didn’t think this started so early on in life. This raises concerns about our policies on antibiotics use, along with hygiene and infection control practices in healthcare facilities.”
The impact of the study in informing current practices in some of the hospitals was also highlighted by Dr. Fatima Modibbo, who co-led the study in Kano, Nigeria: “Prior to the start of the research at the hospital in Kano, blood cultures were not routinely implemented. However, during the study we were able to identify bacterial resistance patterns in blood cultures of neonates presenting with sepsis that led to life saving changes in empirical drug treatments and a reduction in the neonatal mortality rates.”

Although Aduhelm, a monoclonal antibody targeting amyloid beta (Aβ), recently became the first US FDA approved drug for Alzheimer’s disease (AD) based on its ability to decrease Aβ plaque burden in AD patients, its effect on cognitive improvement is still controversial. Moreover, about 40% of the patients treated with this antibody experienced serious side effects including cerebral edemas (ARIA-E) and hemorrhages (ARIA-H) that are likely related to inflammatory responses in the brain when the Aβ antibody binds Fc receptors (FCR) of immune cells such as microglia and macrophages.
These inflammatory side effects can cause neuronal cell death and synapse elimination by activated microglia, and even have the potential to exacerbate cognitive impairment in AD patients. Thus, current Aβ antibody-based immunotherapy holds the inherent risk of doing more harm than good due to their inflammatory side effects.
To overcome these problems, a team of researchers at KAIST in South Korea has developed a novel fusion protein drug, αAβ-Gas6, which efficiently eliminates Aβ via an entirely different mechanism than Aβ antibody-based immunotherapy. In a mouse model of AD, αAβ-Gas6 not only removed Aβ with higher potency, but also circumvented the neurotoxic inflammatory side effects associated with conventional antibody treatments.
Their findings were published on August 4 in Nature Medicine.
“FcR activation by Aβ targeting antibodies induces microglia-mediated Aβ phagocytosis, but it also produces inflammatory signals, inevitably damaging brain tissues,” said paper authors Chan Hyuk Kim and Won-Suk Chung, associate professors in the Department of Biological Sciences at KAIST.
“Therefore, we utilized efferocytosis, a cellular process by which dead cells are removed by phagocytes as an alternative pathway for the clearance of Aβ in the brain,” Prof. Kim and Chung said. “Efferocytosis is accompanied by anti-inflammatory responses to maintain tissue homeostasis. To exploit this process, we engineered Gas6, a soluble adaptor protein that mediates efferocytosis via TAM phagocytic receptors in such a way that its target specificity was redirected from dead cells to Aβ plaques.”
The professors and their team demonstrated that the resulting αAβ-Gas6induced Aβ engulfment by activating not only microglial but also astrocytic phagocytosis since TAM phagocytic receptors are highly expressed by these two major phagocytes in the brain. Importantly, αAβ-Gas6 promoted the robust uptake of Aβ without showing any signs of inflammation and neurotoxicity, which contrasts sharply with the treatment using an Aβ monoclonal antibody. Moreover, they showed that αAβ-Gas6 substantially reduced excessive synapse elimination by microglia, consequently leading to better behavioral rescues in AD model mice.
“By using a mouse model of cerebral amyloid angiopathy (CAA), a cerebrovascular disorder caused by the deposition of Aβ within the walls of the brain’s blood vessels, we also showed that the intrathecal administration of Gas6 fusion protein significantly eliminated cerebrovascular amyloids, along with a reduction of microhemorrhages. These data demonstrate that aAb-Gas6 is a potent therapeutic agent in eliminating Aβ without exacerbating CAA-related microhemorrhages.”
Professors Kim and Chung noted, “We believe our approach can be a breakthrough in treating AD without causing inflammatory side effects and synapse loss. Our approach holds promise as a novel therapeutic platform that is applicable to more than AD. By modifying the target-specificity of the fusion protein, the Gas6-fusion protein can be applied to various neurological disorders as well as autoimmune diseases affected by toxic molecules that should be removed without causing inflammatory responses.”
Professors Kim and Chung founded “Illimis Therapeutics” based on this strategy of designing chimeric Gas6 fusion proteins that would remove toxic aggregates from the nervous system. Through this company, they are planning to further develop various Gas6-fusion proteins not only for Ab but also for Tau to treat AD symptoms.
This work was supported by KAIST and the Korea Health Technology R&D Project that was administered by the Korea Health Industry Development Institute (KHIDI) and the Korea Dementia Research Center (KDRC) funded by the Ministry of Health & Welfare (MOHW) and the Ministry of Science and ICT (MSIT), and KAIST.
Other contributors include Hyuncheol Jung and Se Young Lee, Sungjoon Lim, Hyeong Ryeol Choi, Yeseong Choi, Minjin Kim, Segi Kim, the Department of Biological Sciences, and the Korea Advanced Institute of Science and Technology (KAIST).