Disease
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KAIST Discovers Protein Switch that Turns Anti-Viral Immune Response On and Off
Even after the COVID-19 pandemic, various new infectious diseases continue to emerge, posing ongoing viral threats that demand robust and sustained immune defenses. However, excessive immune reactions can also harm body tissues, causing significant health issues. KAIST and an international research team have discovered a critical protein that acts as a 'switch' regulating immune responses to viruses. This breakthrough is expected to lay the groundwork for future infectious disease responses and autoimmune disease treatment strategies.
KAIST (President Kwang-Hyung Lee) announced on May 14 that a joint research team led by Professor Yoosik Kim from the Department of Chemical and Biomolecular Engineering at KAIST and Professor Seunghee Cha from University of Florida has discovered the mechanism by which double-stranded RNA derived from mitochondria amplifies immune responses. They identified the protein SLIRP as an 'immune switch' that regulates this process, playing a crucial role in both viral infections and autoimmune diseases.
< (From left) Master's candidate Yewon Yang, Professor Yoosik Kim and Ph.D. candidate Doyeong Ku of the Department of Chemical and Biomolecular Engineering >
Autoimmune diseases arise when the immune system fails to differentiate between external pathogens and the body's own molecules, leading to self-directed attacks. Despite extensive research, the precise causes of excessive inflammatory conditions like Sjögren’s syndrome and systemic lupus erythematosus remain unclear, and effective treatments are still limited.
To uncover the molecular mechanisms driving immune hyperactivation and to identify potential regulatory factors, the research team led by Professor Yoosik Kim focused on mitochondrial double-stranded RNA (mt-dsRNA), a genetic immunogenic material produced within cellular organelles. Since mt-dsRNA structurally resembles viral RNA, it can mistakenly trigger immune responses even in the absence of an actual viral infection.
The team discovered that SLIRP, a key regulator of mt-dsRNA, amplifies immune responses by stabilizing the RNA. They confirmed that SLIRP expression increases in experimental models simulating the tissues of autoimmune disease patients and viral infections. Conversely, suppressing SLIRP significantly reduced the immune response, underscoring its role as a critical factor in immune amplification.
This study also demonstrated the dual function of SLIRP in different contexts. In cells infected with human beta coronavirus OC43 and encephalomyocarditis virus (EMCV), SLIRP suppression led to reduced antiviral responses and increased viral replication. Meanwhile, in the blood and salivary gland cells of Sjögren’s syndrome patients, where both SLIRP and mt-dsRNA levels were elevated, suppressing SLIRP alleviated the abnormal immune response.
These findings highlight SLIRP as a key molecular switch that regulates immune responses in both infections and autoimmune diseases.
< Figure 1. Schematic diagram of antiviral signal amplification by SLIRP: SLIRP-based mt-dsRNA induction, cytoplasmic accumulation, and strong interferon response induction by positive feedback of immune response activation. Confirmation of the immune regulatory function of SLIRP in defense against autoimmune diseases Sjögren's syndrome, coronavirus, and encephalomyocarditis virus infection. >
Professor Yoosik Kim remarked, "Through this study, we have identified SLIRP as a crucial protein that drives immune amplification via mt-dsRNAs. Given its dual role in autoimmune diseases and viral infections, SLIRP presents a promising target for immune regulation therapies across various inflammatory disease contexts."
The study, with Ph.D. student Do-Young Ku (first author) and M.S. student Ye-Won Yang (second author) from the Department of Chemical and Biomolecular Engineering at KAIST as primary contributors, was published online in the journal Cell Reports on April 19, 2025.
※ Paper title: SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases※ Main authors: Do-Young Ku (KAIST, first author), Ye-Won Yang (KAIST, second author), Seunghee Cha (University of Florida, corresponding author), Yoosik Kim (KAIST, corresponding author)
This study was supported by the Ministry of Health and Welfare's Public Health Technology Research Program and the National Institutes of Health (NIH) through Research Project (R01) funding.
2025.05.14 View 432 -
Editing Parkinson's Disease – KAIST Makes World's First Discovery of an Inflammatory RNA Editing Enzyme through Co-work with UCL Researchers
< Professor Minee Choi of the Department of Brain and Cognitive Sciences (top left). Professor Sonia Gandhi (top right) and Professor Klenerman of the University College London (bottom right) >
Parkinson's disease (PD) is a neurodegenerative disorder in which the α-synuclein protein abnormally aggregates within brain cells, causing neuronal damage. Through international collaboration, researchers at KAIST have revealed that RNA editing plays a crucial role in regulating neuroinflammation, a key pathology of Parkinson's disease.
KAIST (represented by President Kwang-Hyung Lee) announced on the 27th of April that a research team led by Professor Minee L. Choi from the Department of Brain and Cognitive Sciences, in collaboration with University College London (UCL) and the Francis Crick Institute, discovered that the RNA editing enzyme ADAR1 plays an important role in controlling immune responses in astrocytes, glial cells that trigger protective reactions in the brain, and demonstrated that this mechanism is critically involved in the progression of Parkinson’s disease.
Professor Choi's research team created a co-culture model composed of astrocytes and neurons derived from stem cells originating from Parkinson's disease patients, in order to study the inflammatory responses of brain immune cells. They then treated the model with α-synuclein aggregates, which are known to cause Parkinson’s disease, and analyzed how the immune cells' inflammatory responses changed.
< Figure 1. Schematic diagram of the inflammatory RNA editing model in Parkinson's disease >
As a result, it was found that early pathological forms of α-synuclein, known as oligomers, activated the Toll-like receptor pathway, which acts as a danger sensor in astrocytes, as well as the interferon response pathway, an immune signaling network that combats viruses and pathogens. During this process, the RNA editing enzyme ADAR1 was expressed and transformed into an isoform with an altered protein structure and function.
Notably, the RNA editing activity of ADAR1, which normally functions to regulate immune responses during viral infections by converting adenosine (A) to inosine (I) through a process known as A-to-I RNA editing, was found to be abnormally focused on genes that cause inflammation rather than operating under normal conditions. This phenomenon was observed not only in the patient-derived neuron models but also in postmortem brain tissues from actual Parkinson’s disease patients.
< Figure 2. Experimental design and inflammatory response induction in astrocytes following treatment with α-synuclein oligomers (abnormally folded protein fragments) >
This directly proves that the dysregulation of RNA editing induces chronic inflammatory responses in astrocytes, ultimately leading to neuronal toxicity and pathological progression.
This study is significant in that it newly identified the regulation of RNA editing within astrocytes as a key mechanism behind neuroinflammatory responses. In particular, it suggests that ADAR1 could serve as a novel genetic target for the treatment of Parkinson’s disease.
It is also noteworthy that the study reflected actual pathological characteristics of patients by utilizing patient-specific induced pluripotent stem cell-based precision models for brain diseases.
Professor Minee L. Choi stated, “This study demonstrates that the regulator of inflammation caused by protein aggregation operates at the new layer of RNA editing, offering a completely different therapeutic strategy from existing approaches to Parkinson's disease treatment." She further emphasized, “RNA editing technology could become an important turning point in the development of therapeutics for neuroinflammation.”
< Figure 3. When treated with α-synuclein oligomers, the causative agent of Parkinson's disease, A-to-I RNA editing is induced to change genetic information by ADAR in patient-derived stem cell-differentiated glial cells, confirming that α-synuclein is likely to be associated with the progression of Parkinson's disease through RNA editing >
This study was published in Science Advances on April 11, with Professor Choi listed as a co-first author.
Paper Title: Astrocytic RNA editing regulates the host immune response to alpha-synuclein, Science Advances Vol.11, Issue 15. (DOI:10.1126/sciadv.adp8504)
Lead Authors: Karishma D’Sa (UCL, Co-First Author), Minee L. Choi (KAIST, Co-First Author), Mina Ryten (UCL, Corresponding Author), Sonia Gandhi (Francis Crick Institute, University of Cambridge, Corresponding Author)
This research was supported by the Brain Research Program and the Excellent Young Researcher Program of the National Research Foundation of Korea, as well as KAIST’s Daekyo Cognitive Enhancement Program.
2025.05.02 View 1558 -
KAIST Develops Retinal Therapy to Restore Lost Vision
Vision is one of the most crucial human senses, yet over 300 million people worldwide are at risk of vision loss due to various retinal diseases. While recent advancements in retinal disease treatments have successfully slowed disease progression, no effective therapy has been developed to restore already lost vision—until now. KAIST researchers have successfully developed a novel drug to restore vision.
< Photo 1. (From left) Ph.D. candidate Museong Kim, Professor Jin Woo Kim, and Dr. Eun Jung Lee of KAIST Department of Biological Sciences >
KAIST (represented by President Kwang Hyung Lee) announced on the 30th of March that a research team led by Professor Jin Woo Kim from the Department of Biological Sciences has developed a treatment method that restores vision through retinal nerve regeneration.
The research team successfully induced retinal regeneration and vision recovery in a disease-model mouse by administering a compound that blocks the PROX1 (prospero homeobox 1) protein, which suppresses retinal regeneration. Furthermore, the effect lasted for more than six months.
This study marks the first successful induction of long-term neural regeneration in mammalian retinas, offering new hope to patients with degenerative retinal diseases who previously had no treatment options.
As the global population continues to age, the number of retinal disease patients is steadily increasing. However, no treatments exist to restore damaged retinas and vision. The primary reason for this is the mammalian retina's inability to regenerate once damaged.
Studies on cold-blooded animals, such as fish—known for their robust retinal regeneration—have shown that retinal injuries trigger Müller glia cells to dedifferentiate into retinal progenitor cells, which then generate new neurons. However, in mammals, this process is impaired, leading to permanent retinal damage.
< Figure 1. Schematic diagram of the mechanism of retinal regeneration through inhibition of PROX1 migration. PROX1 protein secreted from retinal damaged retinal neurons transfers to Müllerglia and inhibits dedifferentiation into neural progenitor cells and neural regeneration. When PROX1 is captured outside the cells by an antibody against PROX1 and its transfer to Müllerglia is interfered, dedifferentiation of Müllerglia cells and retinal regeneration processes are resumed, restoring visual function. >
Through this study, the research team identified the PROX1 protein as a key inhibitor of Müller glia dedifferentiation in mammals. PROX1 is a protein found in neurons of the retina, hippocampus, and spinal cord, where it suppresses neural stem cell proliferation and promotes differentiation into neurons.
The researchers discovered that PROX1 accumulates in damaged mouse retinal Müller glia, but is absent in the highly regenerative Müller glia of fish. Furthermore, they demonstrated that the PROX1 found in Müller glia is not synthesized internally but rather taken up from surrounding neurons, which fail to degrade and instead secrete the protein.
Based on this finding, the team developed a method to restore Müller glia’s regenerative ability by eliminating extracellular PROX1 before it reaches these cells.
< Figure 2. Retinal regeneration and visual recovery in a retinitis pigmentosa model mouse through Anti-PROX1 gene therapy. After administration of adeno-associated virus expressing PROX1 neutralizing antibodies (AAV2-Anti-PROX1) to the eyes of RP1 retinitis pigmentosa model mice with vision loss, the photoreceptor cell layer of the retina is restored (A) and vision is restored (B). >
This approach involves using an antibody that binds to PROX1, developed by Celliaz Inc., a biotech startup founded by Professor Jin Woo Kim’s research lab. When administered to disease-model mouse retinas, this antibody significantly promoted neural regeneration. Additionally, when delivered, the antibody gene to the retinas of retinitis pigmentosa disease model mice, it enabled sustained retinal regeneration and vision restoration for over six months.
The retinal regeneration-inducing therapy is currently being developed by Celliaz Inc. for application in various degenerative retinal diseases that currently lack effective treatments. The company aims to begin clinical trials by 2028.
This study was co-authored by Dr. Eun Jung Lee of Celliaz Inc. and Museong Kim, a Ph.D. candidate at KAIST, as joint first authors. The findings were published online on March 26 in the international journal Nature Communications. (Paper Title: Restoration of retinal regenerative potential of Müller glia by disrupting intercellular Prox1 transfer | DOI: 10.1038/s41467-025-58290-8)
Dr. Eun Jung Lee stated, "We are about completing the optimization of the PROX1-neutralizing antibody (CLZ001) and move to preclinical studies before administering it to retinal disease patients. Our goal is to provide a solution for patients at risk of blindness who currently lack proper treatment options."
This research was supported by research funds from Korean National Research Foundation (NRF) and the Korea Drug Development Foundation (KDDF).
2025.03.31 View 6646 -
KAIST to Collaborate with AT&C to Take Dominance over Dementia
< Photo 1. (From left) KAIST Dean of the College of Natural Sciences Daesoo Kim, KAIST President Kwang Hyung Lee, AT&C Chairman Ki Tae Lee, AT&C CEO Jong-won Lee >
KAIST (President Kwang Hyung Lee) announced on January 9th that it signed a memorandum of understanding for a comprehensive mutual cooperation with AT&C (CEO Jong-won Lee) at its Seoul Dogok Campus to expand research investment and industry-academia cooperation in preparation for the future cutting-edge digital bio era.
Senile dementia is a rapidly increasing brain disease that affects 10% of the elderly population aged 65 and older, and approximately 38% of those aged 85 and older suffer from dementia. Alzheimer's disease is the most common dementia in the elderly and its prevalence has been increasing rapidly in the population of over 40 years of age. However, an effective treatment is yet to be found.
The Korean government is investing a total of KRW 1.1 trillion in dementia R&D projects from 2020 to 2029, with the goal of reducing the rate of increase of dementia patients by 50%. Since it takes a lot of time and money to develop effective and affordable medicinal dementia treatments, it is urgent to work on the development of digital treatments for dementia that can be applied more quickly.
AT&C, a digital healthcare company, has already received approval from the Ministry of Food and Drug Safety (MFDS) for its device for antidepressant treatment based on transcranial magnetic stimulation (TMS) using magnetic fields and is selling it domestically and internationally. In addition, it has developed the first Alzheimer's dementia treatment device in Korea and received MFDS approval for clinical trials. After passing phase 1 to evaluate safety and phase 2 to test efficacy on some patients, it is currently conducting phase 3 clinical trials to test efficacy on a larger group of patients.
This dementia treatment device is equipped with a system that combines non-invasive electronic stimulations (TMS electromagnetic stimulator) and digital therapeutic prescription (cognitive learning programs) to provide precise, automated treatment by applying AI image analysis and robotics technology.
Through this agreement, KAIST and AT&C have agreed to cooperate with each other in the development of innovative digital treatment equipment for brain diseases. Through research collaboration with KAIST, AT&C will be able to develop technology that can be widely applied to Parkinson's disease, stroke, mild cognitive impairment, sleep disorders, etc., and will develop portable equipment that can improve brain function and prevent dementia at home by utilizing KAIST's wearable technology.
To this end, AT&C plans to establish a digital healthcare research center at KAIST by supporting research personnel and research expenses worth approximately 3 billion won with the goal of developing cutting-edge digital equipment within 3 years.
The digital equipment market is expected to grow at a compounded annual growth rate of 22.1% from 2023 to 2033, reaching a market size of $1.9209 trillion by 2033.
< Photo 2. (From left) Dean of the KAIST College of Natural Sciences Daesoo Kim, Professor Young-joon Lee, Professor Minee Choi of the KAIST Department of Brain and Cognitive Sciences, KAIST President Kwang Hyung Lee, Chairman Ki Tae Lee, CEO Jong-won Lee, and Headquarters Director Ki-yong Na of AT&C >
CEO Jong-won Lee said, “AT&C is playing a leading role in the treatment of Alzheimer’s disease using TMS (transcranial magnetic stimulation) technology. Through this agreement with KAIST, we will do our best to create a new paradigm for brain disease treatment and become a platform company that can lead future medical devices and medical technology.”
Former Samsung Electronics Vice Chairman Ki Tae Lee, a strong supporter of this R&D project, said, “Through this agreement with KAIST, we plan to prepare for a new future by combining the technologies AT&C has developed so far with KAIST’s innovative and differentiated technologies.”
KAIST President Kwang Hyung Lee emphasized, “Through this collaboration, KAIST expects to build a world-class digital therapeutics infrastructure for treating brain diseases and contribute greatly to further strengthening Korea’s competitiveness in the biomedical field.”
The signing ceremony was attended by KAIST President Kwang Hyung Lee, the Dean of KAIST College of Natural Sciences Daesoo Kim, AT&C CEO Lee Jong-won, and the current Chairman of AT&C, Ki Tae Lee, former Vice Chairman of Samsung Electronics.
2025.01.09 View 2923 -
A Korean research team develops a new clinical candidate for fatty liver disease
A team of Korean researchers have succeeded in developing a new drug candidate for the treatment of non-alcoholic fatty liver disease (NAFLD) acting on peripheral tissues. To date, there has not been an optimal treatment for non-alcoholic steatohepatitis (NASH), and this discovery is expected to set the grounds for the development of new drugs that can safely suppress both liver fat accumulation and liver fibrosis at the same time.
A joint research team led by Professor Jin Hee Ahn from Gwangju Institute of Science and Technology (GIST) and Professor Hail Kim from the KAIST Graduate School of Medical Science and Engineering developed a new chemical that can suppress disease-specific protein (HTR2A) through years of basic research. The team also revealed to have verified its efficacy and safety through preclinical tests (animal tests) at JD Bioscience Inc., a start-up company founded by Professor Ahn.
Although NAFLD has a prevalence rate as high as 20-30%, and about 5% of the global adult population suffers from NASH, there are no commercial drugs targeting them to date. NAFLD is a chronic disease that starts from the fatty liver and progresses into steatohepatitis, fibrosis, cirrhosis, and liver cancer. The mortality rate of patients increases with accompanied cardiovascular diseases and liver-related complications, and appropriate treatment in the early stage is hence necessary.
< Figure 1. Strategy and history of 5HT2A antagonists. Library and rational design for the development of compound 11c as a potent 5HT2A antagonist. Previous research efforts were discontinued due to limited oral absorption and safety. A therapeutic candidate to overcome this problem was identified and phase 1 clinical trials are currently in progress. >
The new synthetic chemical developed by the joint GIST-KAIST research is an innovative drug candidate that shows therapeutic effects on NASH based on a dual action mechanism that inhibits the accumulation of fat in the liver and liver fibrosis by suppressing the serotonin receptor protein 5HT2A.
The research team confirmed its therapeutic effects in animal models for NAFLD and NASH, in which hepatic steatosis and liver fibrosis* caused by fat accumulation in the liver were suppressed simultaneously by 50-70%.
*fibrosis: stiffening of parts of the liver, also used as a major indicator to track the prognosis of steatosis
The research team explained that the material was designed with optimal polarity and lipid affinity to minimize its permeability across the blood-brain barrier. It therefore does not affect the brain, and causes little side effects in the central nervous system (CNS) such as depression and suicidal ideations, while demonstrating excellent inhibition on its target protein present in tissues outside brain (IC50* = 14 nM). The team also demonstrated its superior efficacy in improving liver fibrosis when compared to similar drugs in the phase 3 clinical trial.
*IC50 (half maximal inhibitory concentration): the concentration at which a chemical suppresses 50% of a particular biological function
< Figure 2. GM-60106 (11c)'s effect on obesity: When GM-60106 was administered to an obese animal model (mice) for 2 months, body weight, body fat mass, and blood sugar were significantly reduced (a-d). In addition, the steatohepatitis level (NAFLD Activity Score) and the expression of genes of the treated mice involved in adipogenesis along with blood/liver fat decreased (e-h) >
Based on the pharmacological data obtained through preclinical trials, the team evaluated the effects of the drug on 88 healthy adults as part of their phase 1 clinical trial, where the side effects and the safe dosage of a drug are tested against healthy adults. Results showed no serious side effects and a good level of drug safety.
In addition, a preliminary efficacy evaluation on eight adults with steatohepatitis is currently underway.
Professor Jin Hee Ahn said, “The aim of this research is to develop a treatment for NASH with little side effects and guaranteed safety by developing a new target. The developed chemical is currently going through phase 1 of the global clinical trial in Australia through JD Bioscience Inc., a bio venture company for innovative drug development.” he added, “The candidate material the research team is currently developing shows not only a high level of safety and preventative effects by suppressing fat accumulation in the liver, but also a direct therapeutic effect on liver fibrosis. This is a strength that distinguishes our material from other competing drugs.”
< Figure 3. Efficacy of GM-60106 (11c) on liver fibrosis: When GM-60106 was administered to a steatohepatitis model (mice) for 3 months, the expression of genes associated with tissue fibrosis was significantly reduced (b-c). As a result of a detailed analysis of the tissues of the animal model, it was confirmed that the rate of tissue fibrosis was reduced and the expression rate of genes related to tissue fibrosis and inflammation was also significantly reduced (e-h). >
Professor Hail Kim from KAIST said, “Until now, this disease did not have a method of treatment other than weight control, and there has been no attempt to develop a drug that can be used for non-obese patients.” He added, “Through this research, we look forward to the development of various treatment techniques targeting a range of metabolic diseases including NASH that do not affect the weight of the patient.”
This study, conducted together by the research teams led by Professor Ahn from GIST and Professor Kim from KAIST, as well as the research team from JD Bioscience Inc., was supported by the Ministry of Science and ICT, and the National New Drug Development Project. The results of this research were published by Nature Communications on January 20.
The team also presented the results of their clinical study on the candidate material coded GM-60106 targeting metabolic abnormality-related MASH* at NASH-TAG Conference 2024, which was held in Utah for three days starting on January 4, which was selected as an excellent abstract.
*MASH (Metabolic Dysfunction-Associated Steatohepatitis): new replacement term for NASH
2024.02.21 View 7748 -
Establishing a novel strategy to tackle Huntington’s disease
A platform to take on the Huntington’s disease via an innovative approach established by KAIST’s researchers through international collaboration with scientists in the Netherlands, France, and Sweden.
Through an international joint research effort involving ProQR Therapeutics of the Netherlands, Université Grenoble Alpes of France, and KTH Royal Institute of Technology of Sweden, Professor Ji-Soon Song's research team in the Department of Biological Sciences and KAIST Institute for BioCentury of KAIST, established a noble strategy to treat Huntington's disease. The new works showed that the protein converted from disease form to its disease-free form maintains its original function, providing new roadblocks to approach Huntington’s disease.
This research, titled, “A pathogenic-proteolysis resistant huntingtin isoform induced by an antisense oligonucleotide maintains huntingtin function”, co-authored by Hyeongju Kim, was published in the online edition of 'Journal of Clinical Investigation Insight' on August 9, 2022.
Huntington's disease is a dominantly inherited neurodegenerative disease and is caused by a mutation in a protein called ‘huntingtin’, which adds a distinctive feature of an expanded stretch of glutamine amino acids called polyglutamine to the protein. It is estimated that one in every 10,000 have Huntington's disease in United States. The patients would suffer a decade of regression before death, and, thus far, there is no known cure for the disease.
The cleavage near the stretched polyglutamine in mutated huntingtin is known to be the cause of the Huntington’s disease. However, as huntingtin protein is required for the development and normal function of the brain, it is critical to specifically eliminate the disease-causing protein while maintaining the ones that are still normally functioning.
The research team showed that huntingtin delta 12, the converted form of huntingtin that is resistant to developing cleavages at the ends of the protein, the known cause of the Huntington’s disease (HD), alleviated the disease’s symptoms while maintaining the functions of normal huntingtin.
Figure. Huntington's disease resistance huntingtin protein induced by antisense oligonucleotide (AON) is resistant to Caspase-6 cleavage, therefore, does not cause Huntington’s disease while maintaining normal functions of huntingtin.
The research was welcomed as it is sure to fuel innovate strategies to tackle Huntington’s disease without altering the essential function of huntingtin.
This work was supported by a Global Research Lab grant from the National Research Foundation of Korea (NRF) and by a EUREKA Eurostars 2 grant from European Union Horizon 2020.
2022.09.02 View 7211 -
A New Therapeutic Drug for Alzheimer’s Disease without Inflammatory Side Effects
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.
Schematic of a chimeric Gas6 fusion protein. A single chain variable fragment (scFv) of
an Amyloid β (Aβ)-targeting monoclonal antibody is fused with a truncated receptor binding
domain of Gas6, a bridging molecule for the clearance of dead cells via TAM (TYRO3, AXL,
and MERTK) receptors, which are expressed by microglia and astrocytes.
“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-Gas6 induced 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.”
The resulting αAβ-Gas6 clears Aβ oligomers and fibrils without causing neurotoxicity (a-b, neurons: red, and fragmented axons: yellow) and proinflammatory responses (c, TNF release), which are conversely exacerbated by the treatment of an Aβ-targeting monoclonal antibody (Aducanumab).
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.”
The number and total area of Aβ plaques (Thioflavin-T, green) were significantly reduced in αAβ-Gas6-treated AD mouse brains compared to Aducanumab-treated ones (a, b). The cognitive functions of AD model mice were significantly rescued by αAβ-Gas6 treatment, whereas Aducanumab-treated AD mice showed partial rescue in these cognitive tests (c-e).
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).
To receive more up-to-date information on this new development, follow “Illimis Therapeutics” on twitter @Illimistx.
2022.08.05 View 11968 -
KAIST Research Team Proves How a Neurotransmitter may be the Key in Controlling Alzheimer’s Toxicity
With nearly 50 million dementia patients worldwide, and Alzheimers’s disease is the most common neurodegenerative disease. Its main symptom is the impairment of general cognitive abilities, including the ability to speak or to remember. The importance of finding a cure is widely understood with increasingly aging population and the life expectancy being ever-extended. However, even the cause of the grim disease is yet to be given a clear definition.
A KAIST research team in the Department of Chemistry led by professor Mi Hee Lim took on a lead to discovered a new role for somatostatin, a protein-based neurotransmitter, in reducing the toxicity caused in the pathogenic mechanism taken towards development of Alzheimer’s disease. The study was published in the July issue of Nature Chemistry under the title, “Conformational and functional changes of the native neuropeptide somatostatin occur in the presence of copper and amyloid-β”.
According to the amyloid hypothesis, the abnormal deposition of Aβ proteins causes death of neuronal cells. While Aβ agglomerations make up most of the aged plaques through fibrosis, in recent studies, high concentrations of transitional metal were found in the plaques from Alzheimer’s patients.
This suggests a close interaction between metallic ions and Aβ, which accelerates the fibrosis of proteins. Copper in particular is a redox-activating transition metal that can produce large amounts of oxygen and cause serious oxidative stress on cell organelles. Aβ proteins and transition metals can closely interact with neurotransmitters at synapses, but the direct effects of such abnormalities on the structure and function of neurotransmitters are yet to be understood.
Figure 1. Functional shift of somatostatin (SST) by factors in the pathogenesis of Alzheimer's disease.
Figure 2. Somatostatin’s loss-of-function as neurotransmitter. a. Schematic diagram of SST auto-aggregation due to Alzheimer's pathological factors. b. SST’s aggregation by copper ions. c. Coordination-prediction structure and N-terminal folding of copper-SST. d. Inhibition of SST receptor binding specificity by metals.
In their research, Professor Lim’s team discovered that when somatostatin, the protein-based neurotransmitter, is met with copper, Aβ, and metal-Aβ complexes, self-aggregates and ceases to perform its innate function of transmitting neural signals, but begins to attenuate the toxicity and agglomeration of metal-Aβ complexes.
Figure 3. Gain-of-function of somatostatin (SST) in the dementia setting. a. Prediction of docking of SST and amyloid beta. b. SST making metal-amyloid beta aggregates into an amorphous form. c. Cytotoxic mitigation effect of SST. d. SST mitigating the interaction between amyloid beta protein with the cell membrane.
This research, by Dr. Jiyeon Han et al. from the KAIST Department of Chemistry, revealed the coordination structure between copper and somatostatin at a molecular level through which it suggested the agglomeration mechanism, and discovered the effects of somatostatin on Aβ agglomeration path depending on the presence or absence of metals. The team has further confirmed somatostatin’s receptor binding, interactions with cell membranes, and effects on cell toxicity for the first time to receive international attention.
Professor Mi Hee Lim said, “This research has great significance in having discovered a new role of neurotransmitters in the pathogenesis of Alzheimer’s disease.” “We expect this research to contribute to defining the pathogenic network of neurodegenerative diseases caused by aging, and to the development of future biomarkers and medicine,” she added.
This research was conducted jointly by Professor Seung-Hee Lee’s team of KAIST Department of Biological Sciences, Professor Kiyoung Park’s Team of KAIST Department of Chemistry, and Professor Yulong Li’s team of Peking University.
The research was funded by Basic Science Research Program of the National Research Foundation of Korea and KAIST.
For more information about the research team, visit the website: https://sites.google.com/site/miheelimlab/1-professor-mi-hee-lim.
2022.07.29 View 13842 -
A Mathematical Model Shows High Viral Transmissions Reduce the Progression Rates for Severe Covid-19
The model suggests a clue as to when a pandemic will turn into an endemic
A mathematical model demonstrated that high transmission rates among highly vaccinated populations of COVID-19 ultimately reduce the numbers of severe cases. This model suggests a clue as to when this pandemic will turn into an endemic.
With the future of the pandemic remaining uncertain, a research team of mathematicians and medical scientists analyzed a mathematical model that may predict how the changing transmission rate of COVID-19 would affect the settlement process of the virus as a mild respiratory virus.
The team led by Professor Jae Kyoung Kim from the Department of Mathematical Science and Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering used a new approach by dividing the human immune responses to SARS-CoV-2 into a shorter-term neutralizing antibody response and a longer-term T-cell immune response, and applying them each to a mathematical model. Additionally, the analysis was based on the fact that although breakthrough infection may occur frequently, the immune response of the patient will be boosted after recovery from each breakthrough infection.
The results showed that in an environment with a high vaccination rate, although COVID-19 cases may rise temporarily when the transmission rate increases, the ratio of critical cases would ultimately decline, thereby decreasing the total number of critical cases and in fact settling COVID-19 as a mild respiratory disease more quickly.
Conditions in which the number of cases may spike include relaxing social distancing measures or the rise of variants with higher transmission rates like the Omicron variant. This research did not take the less virulent characteristic of the Omicron variant into account but focused on the results of its high transmission rate, thereby predicting what may happen in the process of the endemic transition of COVID-19.
The research team pointed out the limitations of their mathematical model, such as the lack of consideration for age or patients with underlying diseases, and explained that the results of this study must be applied with care when compared against high-risk groups. Additionally, as medical systems may collapse when the number of cases rises sharply, this study must be interpreted with prudence and applied accordingly. The research team therefore emphasized that for policies that encourage a step-wise return to normality to succeed, the sustainable maintenance of public health systems is indispensable.
Professor Kim said, “We have drawn a counter-intuitive conclusion amid the unpredictable pandemic through an adequate mathematical model,” asserting the importance of applying mathematical models to medical research.
Professor Shin said, “Although the Omicron variant has become the dominant strain and the number of cases is rising rapidly in South Korea, it is important to use scientific approaches to predict the future and apply them to policies rather than fearing the current situation.”
The results of the research were published on medRxiv.org on February 11, under the title “Increasing viral transmission paradoxically reduces progression rates to severe COVID-19 during endemic transition.”
This research was funded by the Institute of Basic Science, the Korea Health Industry Development Institute, and the National Research Foundation of Korea.
-PublicationHyukpyo Hong, Ji Yun Noh, Hyojung Lee, Sunhwa Choi, Boseung Choi, Jae Kyung Kim, Eui-Cheol Shin, “Increasing viral transmission paradoxically reduces progression rates to
severe COVID-19 during endemic transition,” medRxiv, February 9, 2022 (doi.org/10.1101/2022.02.09.22270633)
-ProfileProfessor Jae Kyung KimDepartment of Mathematical SciencesKAIST
Professor Eui-Cheol ShinGraduate School of Medical Science and EngineeringKAIST
2022.02.22 View 10277 -
Two Researchers Designated as SUHF Fellows
Professor Taeyun Ku from the Graduate School of Medical Science and Engineering and Professor Hanseul Yang from the Department of Biological Sciences were nominated as 2021 fellows of the Suh Kyungbae Foundation (SUHF).
SUHF selected three young promising scientists from 53 researchers who are less than five years into their careers. A panel of judges comprised of scholars from home and abroad made the final selection based on the candidates’ innovativeness and power to influence. Professor You-Bong Hyun from Seoul National University also won the fellowship.
Professor Ku’s main topic is opto-connectomics. He will study ways to visualize the complex brain network using innovative technology that transforms neurons into optical elements.
Professor Yang will research the possibility of helping patients recover from skin diseases or injuries without scars by studying spiny mouse genes.
SUHF was established by Amorepacific Group Chairman Suh Kyungbae in 2016 with 300 billion KRW of his private funds. Under the vision of ‘contributing to humanity by supporting innovative discoveries of bioscience researchers,’ the foundation supports promising Korean scientists who pioneer new fields of research in biological sciences.
From 2017 to this year, SUHF has selected 20 promising scientists in the field of biological sciences. Selected scientists are provided with up to KRW 500 million each year for five years. The foundation has provided a total of KRW 48.5 billion in research funds to date.
2021.09.15 View 8622 -
A Study Reveals What Triggers Lung Damage during COVID-19
A longitudinal study of macrophages from SARS-CoV-2 infected lungs offers new insights into dynamic immunological changes
A KAIST immunology research team found that a specific subtype of macrophages that originated from blood monocytes plays a key role in the hyper-inflammatory response in SARS-CoV-2 infected lungs, by performing single-cell RNA sequencing of bronchoalveolar lavage fluid cells. This study provides new insights for understanding dynamic changes in immune responses to COVID-19.
In the early phase of COVID-19, SARS-CoV-2 infected lung tissue and the immediate defense system is activated. This early and fast response is called ‘innate immunity,’ provided by immune cells residing in lungs. Macrophages are major cell types of the innate immune system of the lungs, and newly differentiated macrophages originating from the bloodstream also contribute to early defenses against viruses.
Professor Su-Hyung Park and his collaborators investigated the quantitative and qualitative evaluation of immune responses in the lungs of SARS-CoV-2 infected ferrets. To overcome the limitations of research using patient-originated specimens, the researchers used a ferret infection model to obtain SARS-CoV-2 infected lungs sequentially with a defined time interval.
The researchers analyzed the 10 subtypes of macrophages during the five-day course of SARS-CoV-2 infection, and found that infiltrating macrophages originating from activated monocytes in the blood were key players for viral clearance as well as damaged lung tissue. Moreover, they found that the differentiation process of these inflammatory macrophages resembled the immune responses in the lung tissue of severe COVID-19 patients.
Currently, the research team is conducting a follow-up study to identify the dynamic changes in immune responses during the use of immunosuppressive agents to control hyper-inflammatory response called ‘cytokine storm’ in patients with COVID-19.
Dr. Jeong Seok Lee, the chief medical officer at Genome Insight Inc., explained, “Our analysis will enhance the understanding of the early features of COVID-19 immunity and provide a scientific background for the more precise use of immunosuppressive agents targeting specific macrophage subtypes.”
“This study is the first longitudinal study using sequentially obtained immune cells originating from SARS-CoV-2 infected lungs. The research describes the innate immune response to COVID-19 using single cell transcriptome data and enhances our understanding of the two phases of inflammatory responses,” Professor Park said.
This work was supported by the Ministry of Health and Welfare and KAIST, and was published in Nature Communications on July 28.
-PublicationSu-Hyung Park, Jeong Seok Lee, Su-Hyung Park et al. “Single-cell transcriptome of bronchoalverolar lavage fluid reveals sequential change of macrophages during SARS-CoV-2 infection in ferrets” Nature Communications (https://doi.org/10.1038/s41467-021-24807-0)
-ProfileProfessor Su-Hyung ParkLaboratory of Translational Immunology and Vaccinologyhttps://ltiv.kaist.ac.kr/
Graduate School of Medical Science and EngineeringKAIST
2021.08.04 View 12825 -
Hydrogel-Based Flexible Brain-Machine Interface
The interface is easy to insert into the body when dry, but behaves ‘stealthily’ inside the brain when wet
Professor Seongjun Park’s research team and collaborators revealed a newly developed hydrogel-based flexible brain-machine interface. To study the structure of the brain or to identify and treat neurological diseases, it is crucial to develop an interface that can stimulate the brain and detect its signals in real time. However, existing neural interfaces are mechanically and chemically different from real brain tissue. This causes foreign body response and forms an insulating layer (glial scar) around the interface, which shortens its lifespan.
To solve this problem, the research team developed a ‘brain-mimicking interface’ by inserting a custom-made multifunctional fiber bundle into the hydrogel body. The device is composed not only of an optical fiber that controls specific nerve cells with light in order to perform optogenetic procedures, but it also has an electrode bundle to read brain signals and a microfluidic channel to deliver drugs to the brain.
The interface is easy to insert into the body when dry, as hydrogels become solid. But once in the body, the hydrogel will quickly absorb body fluids and resemble the properties of its surrounding tissues, thereby minimizing foreign body response.
The research team applied the device on animal models, and showed that it was possible to detect neural signals for up to six months, which is far beyond what had been previously recorded. It was also possible to conduct long-term optogenetic and behavioral experiments on freely moving mice with a significant reduction in foreign body responses such as glial and immunological activation compared to existing devices.
“This research is significant in that it was the first to utilize a hydrogel as part of a multifunctional neural interface probe, which increased its lifespan dramatically,” said Professor Park. “With our discovery, we look forward to advancements in research on neurological disorders like Alzheimer’s or Parkinson’s disease that require long-term observation.”
The research was published in Nature Communications on June 8, 2021. (Title: Adaptive and multifunctional hydrogel hybrid probes for long-term sensing and modulation of neural activity) The study was conducted jointly with an MIT research team composed of Professor Polina Anikeeva, Professor Xuanhe Zhao, and Dr. Hyunwoo Yook.
This research was supported by the National Research Foundation (NRF) grant for emerging research, Korea Medical Device Development Fund, KK-JRC Smart Project, KAIST Global Initiative Program, and Post-AI Project.
-PublicationPark, S., Yuk, H., Zhao, R. et al. Adaptive and multifunctional hydrogel hybrid probes for long-term sensing and modulation of neural activity. Nat Commun 12, 3435 (2021). https://doi.org/10.1038/s41467-021-23802-9
-ProfileProfessor Seongjun ParkBio and Neural Interfaces LaboratoryDepartment of Bio and Brain EngineeringKAIST
2021.07.13 View 11747