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Study Finds Interferon Triggers Inflammation in Severe COVID-19
KAIST medical scientists and their colleagues confirmed that the type I interferon response plays a pivotal role in exacerbating inflammation in severe COVID-19 cases. Severe COVID-19 has been shown to be caused by a hyper-inflammatory response. Particularly, inflammatory cytokines secreted by classical monocytes and macrophages are believed to play a crucial role in the severe progression of COVID-19. A new single-cell RNA sequencing analysis of more than 59,000 cells from three different patient cohorts provided a detailed look at patients’ immune responses in severe cases of COVID-19. The results suggest that patients with severe cases of COVID-19 experience increased regulation of the type I interferon (IFN-I) inflammation-triggering pathway, a signature that the researchers also observed in patients hospitalized with severe cases of influenza. Their findings suggest that anti-inflammatory treatment strategies for COVID-19 should also be aimed toward the IFN-I signaling pathway, in addition to targeting inflammatory molecules such as TNF, IL-1, and IL-6, which have been associated with COVID-19. The research team under Professor Eui-Cheol Shin from the Graduate School of Medical Science and Engineering sequenced the RNA from a total of 59,572 blood cells obtained from four healthy donors, eight patients with mild or severe COVID-19, and five patients with severe influenza. By comparison, patients with severe cases of influenza showed increased expression of various IFN-stimulated genes, but did not experience TNF/IL-1 responses as seen in COVID-19 patients. Unlike the flu cohort, patients in the severe COVID-19 cohort exhibited the IFN-I signature concurrently with TNF/IL-1-driven inflammation – a combination also not seen in patients with milder cases of COVID-19. Their result, along with past mouse studies that highlight how the timing of IFN-I expression is critical to determining the outcome of SARS, support targeting IFN-I as a potential treatment strategy for severe COVID-19. Professor Shin said, “This research provides insights for designing therapeutic options for COVID-19 by investigating very closely how the immune cells of COVDI-19 patients develop. We will continue to conduct research on novel therapeutic immune mechanisms and target therapeutic anti-inflammatory medication to improve the survival of severe COVID-19 patients.” This study, conducted in collaboration with Severance Hospital at Yonsei University, Asan Medical Center, and Chungbuk National University, was featured in Science Immunology on July 10. This work was funded by Samsung Science and Technology Foundation and SUHF Fellowship. -PublicationScience Immunology 10 Jul 2020:Vol. 5, Issue 49, eabd1554DOI: 10.1126/sciimmunol.abd1554 -ProfileProfessorEui-Cheol ShinGraduate School of Medical Science and EngineeringLaboratory of Immunology & Infectious Diseases (http://liid.kaist.ac.kr/)email@example.comKAIST
Accurate Detection of Low-Level Somatic Mutation in Intractable Epilepsy
KAIST medical scientists have developed an advanced method for perfectly detecting low-level somatic mutation in patients with intractable epilepsy. Their study showed that deep sequencing replicates of major focal epilepsy genes accurately and efficiently identified low-level somatic mutations in intractable epilepsy. According to the study, their diagnostic method could increase the accuracy up to 100%, unlike the conventional sequencing analysis, which stands at about 30% accuracy. This work was published in Acta Neuropathologica. Epilepsy is a neurological disorder common in children. Approximately one third of child patients are diagnosed with intractable epilepsy despite adequate anti-epileptic medication treatment. Somatic mutations in mTOR pathway genes, SLC35A2, and BRAF are the major genetic causes of intractable epilepsies. A clinical trial to target Focal Cortical Dysplasia type II (FCDII), the mTOR inhibitor is underway at Severance Hospital, their collaborator in Seoul, Korea. However, it is difficult to detect such somatic mutations causing intractable epilepsy because their mutational burden is less than 5%, which is similar to the level of sequencing artifacts. In the clinical field, this has remained a standing challenge for the genetic diagnosis of somatic mutations in intractable epilepsy. Professor Jeong Ho Lee’s team at the Graduate School of Medical Science and Engineering analyzed paired brain and peripheral tissues from 232 intractable epilepsy patients with various brain pathologies at Severance Hospital using deep sequencing and extracted the major focal epilepsy genes. They narrowed down target genes to eight major focal epilepsy genes, eliminating almost all of the false positive calls using deep targeted sequencing. As a result, the advanced method robustly increased the accuracy and enabled them to detect low-level somatic mutations in unmatched Formalin Fixed Paraffin Embedded (FFPE) brain samples, the most clinically relevant samples. Professor Lee conducted this study in collaboration with Professor Dong Suk Kim and Hoon-Chul Kang at Severance Hospital of Yonsei University. He said, “This advanced method of genetic analysis will improve overall patient care by providing more comprehensive genetic counseling and informing decisions on alternative treatments.” Professor Lee has investigated low-level somatic mutations arising in the brain for a decade. He is developing innovative diagnostics and therapeutics for untreatable brain disorders including intractable epilepsy and glioblastoma at a tech-startup called SoVarGen. “All of the technologies we used during the research were transferred to the company. This research gave us very good momentum to reach the next phase of our startup,” he remarked. The work was supported by grants from the Suh Kyungbae Foundation, a National Research Foundation of Korea grant funded by the Ministry of Science and ICT, the Korean Health Technology R&D Project from the Ministry of Health & Welfare, and the Netherlands Organization for Health Research and Development. (Figure: Landscape of somatic and germline mutations identified in intractable epilepsy patients. a Signaling pathways for all of the mutated genes identified in this study. Bold: somatic mutation, Regular: germline mutation. b The distribution of variant allelic frequencies (VAFs) of identified somatic mutations. c The detecting rate and types of identified mutations according to histopathology. Yellow: somatic mutations, green: two-hit mutations, grey: germline mutations.)
Newly Identified Meningeal Lymphatic Vessels Answers the Key Questions on Brain Clearance
(Figure: Schematic images of location and features of meningeal lymphatic vessels and their changes associated with ageing.) Just see what happens when your neighborhood’s waste disposal system is out of service. Not only do the piles of trash stink but they can indeed hinder the area’s normal functioning. That is also the case when the brain’s waste management is on the blink. The buildup of toxic proteins in the brain causes a massive damage to the nerves, leading to cognitive dysfunction and increased probability of developing neurodegenerative disorders such as Alzheimer's disease. Though the brain drains its waste via the cerebrospinal fluid (CSF), little has been understood about an accurate route for the brain’s cleansing mechanism. Medical scientists led by Professor Gou Young Koh at the Graduate School of Medical Science and Engineering have reported the basal side of the skull as the major route, so called “hotspot” for CSF drainage. They found that basal meningeal lymphatic vessels (mLVs) function as the main plumbing pipes for CSF. They confirmed macromolecules in the CSF mainly runs through the basal mLVs. Notably, the team also revealed that the brain’s major drainage system, specifically basal mLVs are impaired with aging. Their findings have been reported in the journal Nature on July 24. Throughout our body, excess fluids and waste products are removed from tissues via lymphatic vessels. It was only recently discovered that the brain also has a lymphatic drainage system. mLVs are supposed to carry waste from the brain tissue fluid and the CSF down the deep cervical lymph nodes for disposal. Still scientist are left with one perplexing question — where is the main exit for the CSF? Though mLVs in the upper part of the skull (dorsal meningeal lymphatic vessels) were reported as the brain’s clearance pathways in 2014, no substantial drainage mechanism was observed in that section. “As a hidden exit for CSF, we looked into the mLVs trapped within complex structures at the base of the skull,” says Dr. Ji Hoon Ahn, the first author of this study. The researchers used several techniques to characterize the basal mLVs in detail. They used a genetically engineered lymphatic-reporter mouse model to visualize mLVs under a fluorescence microscope. By performing a careful examination of the mice skull, they found distinctive features of basal mLVs that make them suitable for CSF uptake and drainage. Just like typical functional lymphatic vessels, basal mLVs are found to have abundant lymphatic vessel branches with finger-like protrusions. Additionally, valves inside the basal mLVs allow the flow to go in one direction. In particular, they found that the basal mLVs are closely located to the CSF. Dr. Hyunsoo Cho, the first author of this study explains, “All up, it seemed a solid case that basal mLVs are the brain’s main clearance pathways. The researchers verified such specialized morphologic characteristics of basal mLVs indeed facilitate the CSF uptake and drainage. Using CSF contrast-enhanced magnetic resonance imaging in a rat model, they found that CSF is drained preferentially through the basal mLVs. They also utilized a lymphatic-reporter mouse model and discovered that fluorescence-tagged tracer injected into the brain itself or the CSF is cleared mainly through the basal mLVs. Jun-Hee Kim, the first author of this study notes, “We literally saw that the brain clearance mechanism utilizing basal outflow route to exit the skull. It has long been suggested that CSF turnover and drainage declines with ageing. However, alteration of mLVs associated with ageing is poorly understood. In this study, the researchers observed changes of mLVs in young (3-month-old) and aged (24~27-months-old) mice. They found that the structure of the basal mLVs and their lymphatic valves in aged mice become severely flawed, thus hampering CSF clearance. The corresponding author of this study, Dr. Koh says, “By characterizing the precise route for fluids leaving the brain, this study improves our understanding on how waste is cleared from the brain. Our findings also provide further insights into the role of impaired CSF clearance in the development of age-related neurodegenerative diseases.” Many current therapies for Alzheimer’s disease target abnormally accumulated proteins, such as beta-amyloid. By mapping out a precise route for the brain’s waste clearance system, this study may be able to help find ways to improve the brain’s cleansing function. Such breakthrough might become quite a sensational strategy for eliminating the buildup of aging-related toxic proteins. “It definitely warrants more extensive investigation of mLVs in patients with age-related neurodegenerative disease such as Alzheimer’s disease prior to clinical investigation,” adds Professor Koh.
Deciphering Brain Somatic Mutations Associated with Alzheimer's Disease
Researchers have found a potential link between non-inherited somatic mutations in the brain and the progression of Alzheimer’s disease Researchers have identified somatic mutations in the brain that could contribute to the development of Alzheimer’s disease (AD). Their findings were published in the journal Nature Communications last week. Decades worth of research has identified inherited mutations that lead to early-onset familial AD. Inherited mutations, however, are behind at most half the cases of late onset sporadic AD, in which there is no family history of the disease. But the genetic factors causing the other half of these sporadic cases have been unclear. Professor Jeong Ho Lee at the Graduate School of Medical Science and Engineering and colleagues analysed the DNA present in post-mortem hippocampal formations and in blood samples from people aged 70 to 96 with AD and age-matched controls. They specifically looked for non-inherited somatic mutations in their brains using high-depth whole exome sequencing. The team developed a bioinformatics pipeline that enabled them to detect low-level brain somatic single nucleotide variations (SNVs) – mutations that involve the substitution of a single nucleotide with another nucleotide. Brain somatic SNVs have been reported on and accumulate throughout our lives and can sometimes be associated with a range of neurological diseases. The number of somatic SNVs did not differ between individuals with AD and non-demented controls. Interestingly, somatic SNVs in AD brains arise about 4.8 times more slowly than in blood. When the team performed gene-set enrichment tests, 26.9 percent of the AD brain samples had pathogenic brain somatic SNVs known to be linked to hyperphosphorylation of tau proteins, which is one of major hallmarks of AD. Then, they pinpointed a pathogenic SNV in the PIN1 gene, a cis/trans isomerase that balances phosphorylation in tau proteins, found in one AD patient’s brain. They found the mutation was 4.9 time more abundant in AT8-positive – a marker for hyper-phosphorylated tau proteins– neurons in the entorhinal cortex than the bulk hippocampal tissue. Furthermore, in a series of functional assays, they observed the mutation causing a loss of function in PIN1 and such haploinsufficiency increased the phosphorylation and aggregation of tau proteins. “Our study provides new insights into the molecular genetic factors behind Alzheimer’s disease and other neurodegenerative diseases potentially linked to somatic mutations in the brain,” said Professor Lee. The team is planning to expand their study to a larger cohort in order to establish stronger links between these brain somatic mutations and the pathogenesis of Alzheimer’s disease. (Figure 1. Bioinformatic pipeline for detecting low-level brain somatic mutations in AD and non-AD.) (Figure 2. Pathogenic brain somatic mutations associated with tau phosphorylation are significantly enriched in AD brains.) (Figure 3. A pathogenic brain somatic mutation in PIN1 (c. 477 C>T) is a loss-of-function and related functional assays show its haploinsufficiency increases phosphorylation and aggregation of tau.)
Early Genome Catastrophes Can Cause Non-Smoking Lung Cancer
Some teenagers harbor catastrophic changes to their genomes that can lead to lung cancer later on in life, even if they never smoke (Professor Young Seok Ju at the Graduate School of Medical Science and Engineering) Catastrophic rearrangements in the genome occurring as early as childhood and adolescence can lead to the development of lung cancer in later years in non-smokers. This finding, published in Cell, helps explain how some non-smoking-related lung cancers develop. Researchers at KAIST, Seoul National University and their collaborators confirmed that gene fusions in non-smokers mostly occur early on, sometimes as early as childhood or adolescence, and on average about three decades before cancer is diagnosed. The study showed that these mutant lung cells, harboring oncogenic seeds, remain dormant for several decades until a number of further mutations accumulate sufficiently for progression into cancer. This is the first study to reveal the landscape of genome structural variations in lung adenocarcinoma. Lung cancer is the leading cause of cancer-related deaths worldwide, and lung adenocarcinoma is its most common type. Most lung adenocarcinomas are associated with chronic smoking, but about a fourth develop in non-smokers. Precisely what happens in non-smokers for this cancer to develop is not clearly understood. Researchers analyzed the genomes of 138 lung adenocarcinoma patients, including smokers and non-smokers, with whole-genome sequencing technologies. They explored DNA damage that induced neoplastic transformation. Lung adenocarcinomas that originated from chronic smoking, referred to as signature 4-high (S4-high) cancers in the study, showed several distinguishing features compared to smoking-unrelated cancers (S4-low). People in the S4-high group were largely older, men and had more frequent mutations in a cancer-related gene called KRAS. Cancer genomes in the S4-high group were hypermutated with simple mutational classes, such as the substitution, insertion, or deletion of a single base, the building block of DNA. But the story was very different in the S4-low group. Generally, mutational profiles in this group were much more silent than the S4-high group. However, all cancer-related gene fusions, which are abnormally activated from the merging of two originally separate genes, were exclusively observed in the S4-low group. The patterns of genomic structural changes underlying gene fusions suggest that about three in four cases of gene fusions emerged from a single cellular crisis causing massive genomic fragmentation and subsequent imprecise repair in normal lung epithelium. Most strikingly, these major genomic rearrangements, which led to the development of lung adenocarcinoma, are very likely to be acquired decades before cancer diagnosis. The researchers used genomic archaeology techniques to trace the timing of when the catastrophes took place. Researchers started this study seven years ago when they discovered the expression of the KIF5B-RET gene fusion in lung adenocarcinoma for the first time. Professor Young-Seok Ju, co-lead author from the Graduate School of Medical Science and Engineering at KAIST says, “It is remarkable that oncogenesis can begin by a massive shattering of chromosomes early in life. Our study immediately raises a new question: What induces the mutational catastrophe in our normal lung epithelium.” Professor Young Tae Kim, co-lead author from Seoul National University says, “We hope this work will help us get one step closer to precision medicine for lung cancer patients.” The research team plans to further focus on the molecular mechanisms that stimulate complex rearrangements in the body, through screening the genomic structures of fusion genes in other cancer types. This study was supported by the National Research Foundation of Korea (NRF), Korea Health Industry Development Institute (KHIDI), Suh Kyungbae Foundation, the College of Medicine Research Foundations at Seoul National University and others. Figure. (Smoking-unrelated oncogenesis of lung cancers by gene fusions) Publication. Jake June-Koo Lee, Seongyeol Park et al., Tracing Oncogene Rearrangements in the Mutational History of Lung Adenocarcinoma Cell 177, June 13 2019, online publication ahead of print at May 30, 2019 https://doi.org/10.1016/j.cell.2019.05.013 Profile: Prof Young Seok Ju, MD, PhD firstname.lastname@example.org http://julab.kaist.ac.kr Associate Professor Graduate School of Medical Science and Engineering (GSMSE) Korea Advanced Institute of Science and Technology (KAIST) Daejeon 34141, Korea Profile: Prof Young Tae Kim, MD, PhD email@example.com Professor Seoul National University Cancer Research Institute Department of Thoracic and Cardiovascular Surgery Seoul National University Hospital Seoul 03080, Korea
Autophagy in Dendritic Cells Helps Anticancer Activity
Autophagy contributes to the homeostasis of a cell and recently another function of autophagy has been reported. A KAIST research team found that the autophagy of dendritic cells supports T-cell anticancer activity. Autophagy is a process of maintaining cell homeostasis by removing cellular waste and damaged cellular organelles; nevertheless, its role in the presentation of phagocytized tumor-associated antigens remains vague. Meanwhile, dendritic cells are the ones that recognize pathogens or cancer antigens, and induce immune responses in T cells. When cancer cells are killed by radiation or an anticancer drug, dendritic cells absorb and remove them and present antigens on their surface to transfer them to T-cells. Professor Heung Kyu Lee from the Graduate School of Medical Science and Engineering and his team found that the autophagy of dendritic cells plays a key role in T-cell activation and they proposed the principles of enhancing anti-cancer effects. Their experiments showed that T-cell activation of dendritic cells as well as anticancer immune response dropped when there is a deficiency of Atg5 (autophagy-related) in dendritic cells. Interestingly, Atg5-deficient dendritic cells significantly elevated receptor CD36 on the surface of the cells, which increased the phagocytosis of apoptotic tumor cells yet restricted the activation of T-cells. At this time, when introducing antibodies into the system in order to block the receptor CD36, the anti-tumor T-cell response increased substantially while tumor growth declined. Professor Lee said, “This study allowed us to explore the role of autophagy in the anti-cancer immune response of T-cells. We look forward to developing targeted anti-cancer therapies using the receptor CD36.” This research was published in Autophagy (10.1080/15548627.2019.1596493) on March 22, 2019. Figure 1.Mechanism of autophagy in dendritic cells Figure 2. A role of autophagy in dendritic cells
KAIST Identifies the Cause of Sepsis-induced Lung Injury
(Professor Pilhan Kim from the Graduate School of Medical Science and Engineering) A KAIST research team succeeded in visualizing pulmonary microcirculation and circulating cells in vivo with a custom-built 3D intravital lung microscopic imaging system. They found a type of leukocyte called neutrophils aggregate inside the capillaries during sepsis-induced acute lung injury (ALI), leading to disturbances and dead space in blood microcirculation. According to the researchers, this phenomenon is responsible for tissue hypoxia causing lung damage in the sepsis model, and mitigating neutrophils improves microcirculation as well as hypoxia. The lungs are responsible for exchanging oxygen with carbon dioxide gases during the breathing process, providing an essential function for sustaining life. This gas exchange occurs in the alveoli, each surrounded by many capillaries containing the circulating red blood cells. Researchers have been making efforts to observe microcirculation in alveoli, but it has been technically challenging to capture high-resolution images of capillaries and red blood cells inside the lungs that are in constant breathing motion. Professor Pilhan Kim from the Graduate School of Medical Science and Engineering and his team developed an ultra-fast laser scanning confocal microscope and an imaging chamber that could minimize the movement of a lung while preserving its respiratory state. They used this technology to successfully capture red blood cell circulation inside the capillaries of animal models with sepsis. During the process, they found that hypoxia was induced by the increase of dead space inside the lungs of a sepsis model, a space where red blood cells do not circulate. This phenomenon is due to the neutrophils aggregating and trapping inside the capillaries and the arterioles. It was also shown that trapped neutrophils damage the lung tissue in the sepsis model by inhibiting microcirculation as well as releasing reactive oxygen species. Further studies showed that the aggregated neutrophils inside pulmonary vessels exhibit a higher expression of the Mac-1 receptor (CD11b/CD18), which is a receptor involved in intercellular adhesion, compared to the neutrophils that normally circulate. Additionally, they confirmed that Mac-1 inhibitors can improve inhibited microcirculation, ameliorate hypoxia, while reducing pulmonary edema in the sepsis model. Their high-resolution 3D intravital microscope technology allows the real-time imaging of living cells inside the lungs. This work is expected to be used in research on various lung diseases, including sepsis. The research team’s pulmonary circulation imaging and precise analytical techniques will be used as the base technology for developing new diagnostic technologies, evaluating new therapeutic agents for various diseases related to microcirculation. Professor Kim said, “In the ALI model, the inhibition of pulmonary microcirculation occurs due to neutrophils. By controlling this effect and improving microcirculation, it is possible to eliminate hypoxia and pulmonary edema – a new, effective strategy for treating patients with sepsis.” Their 3D intravital microscope technology was commercialized through IVIM Technology, Inc., which is a faculty startup at KAIST. They released an all-in-one intravital microscope model called ‘IVM-CM’ and ‘IVM-C’. This next-generation imaging equipment for basic biomedical research on the complex pathophysiology of various human diseases will play a crucial role in the future global bio-health market. This research, led by Dr. Inwon Park from the Department of Emergency Medicine at Seoul National University Bundang Hospital and formally the Graduate School of Medical Science and Engineering at KAIST, was published in the European Respiratory Journal (2019, 53:1800736) on March 28, 2019. Figure 1. Custom-built high-speed real-time intravital microscope platform Figure 2. Illustrative schematic and photo of a 3D intravital lung microscopic imaging system Figure 3. Aggregation of neutrophils and consequent flow disturbance in pulmonary arteriole in sepsis-induced lung injury
Optimal Immuno-Therapeutic Strategies for Liver Cancer
KAIST medical scientists have presented a heterogeneity of immune cell exhaustion in the cancer environment, providing evidence and rationale for designing optimal strategies for immune checkpoint inhibitors in liver cancer patients. They succeeded in distinguishing the hepatocellular carcinoma group from the exhausted tumor infiltrating immune cell composition of liver cancer patients. The study, conducted in collaboration with Asan Medical Center, confirmed the applicability for liver cancer patients, providing a new path for personalized precision medicine as well as a new model for translational research. Our immune system is able to destroy cancerous cells in our body, however sometimes cancer cells can adapt and mutate, effectively hiding from our immune system. One of the mechanisms that has evolved to prevent eradication by the immune system is to functionally silence effector T cells, termed T-cell exhaustion, that is mainly mediated by immune checkpoint molecules such as PD-1, TIM-3, and LAG-3. Recent breakthroughs and encouraging clinical results with various immune checkpoint inhibitors (ICIs), such as anti-PD-1 monoclonal antibodies (mAbs) and anti-CTLA-4 mAbs, have demonstrated tremendous potential to cure cancers through the immune activation of exhausted T cells. Immune checkpoint inhibitors showed significant clinical benefits for several types of cancers, leading to their wide application in clinical practice. Anti-PD1 blocking antibodies are one of the most representative agents in this class of drug. However, it has been challenging to precisely understand the biological and clinical significance of T-cell exhaustion in cancer. A KAIST research team led by Professor Su-Hyung Park reported the heterogeneity of T-cell exhaustion in hepatocellular carcinoma (HCC) and its potential clinical implications in Gastroenterology on December 4. The team revealed that heterogeneous T-cell exhaustion status is determined by the differential PD-1 expression levels in CD8+ T cells in liver cancer patients. The authors found that tumor-infiltrating CD8+ T cells with high PD-1 expression from liver cancer patients are functionally impaired and co-express other immune checkpoint receptors such as TIM-3 and/or LAG3, compared to those with low PD-1 expression. Moreover, based on these results, the authors suggested that liver cancer patients can be classified into two distinct subgroups. Patients having high PD-1 expression levels in the tumor microenvironment showed more aggressive tumor features and biomarkers predicting a favorable response to anti-PD1 therapy. The research team also demonstrated that only liver cancer patients having high PD-1 expression are susceptible to combined immune checkpoint blockade-based therapies. Prof. Park said, “The new classification of liver cancer patients identified by this study can be utilized as a biomarker to predict the response of current cancer immunotherapy targeting the PD-1 pathway.” He also said they will continue to conduct research on T-cell exhaustion and activation in various types of cancer, which could lead to a better understanding of T-cell response against cancer, thereby providing evidence for future cancer immunotherapy to achieve the ultimate goal to prolong the survival of cancer patients.
Understanding Epilepsy in Pediatric Tumors; New Therapeutic Target of Intractable Epilepsy Identified
Pediatric brain tumors are characterized by frequent complications due to intractable epilepsy compared to adult brain tumors. However, the genetic cause of refractory epilepsy in pediatric brain tumors has not been elucidated yet, and it is difficult to treat patients because the tumors do not respond to existing antiepileptic drugs and debilitate children’s development. A research team led by Professor Jeong Ho Lee of the Graduate School of Medical Science and Engineering has recently identified a neuronal BRAF somatic mutation that causes intrinsic epileptogenicity in pediatric brain tumors. Their research results were published online in Nature Medicine on September 17. The research team studied patients’ tissue diagnosed with ganglioglioma (GG), one of the main causes of tumor-associated intractable epilepsy, and found that the BRAF V600E somatic mutation is involved in the development of neural stem cells by using deep DNA sequencing. This mutation was carried out in an animal model to reproduce the pathology of GG and to observe seizures to establish an animal model for the treatment of epileptic seizures caused by pediatric brain tumors. Using immunohistochemical and transcriptome analysis, they realized that the BRAF V600E mutation that arose in early progenitor cells during embryonic brain formation led to the acquisition of intrinsic epileptogenic properties in neuronal lineage cells, whereas tumorigenic properties were attributed to a high proliferation of glial lineage cells exhibiting the mutation. Notably, researchers found that seizures in mice were significantly alleviated by intraventricular infusion of the BRAF V600E inhibitor, Vemurafenib, a clinical anticancer drug. The authors said, “Our study offers the first direct evidence that the BRAF somatic mutation arising from neural stem cells plays a key role in epileptogenesis in the brain tumor. This study also showed a new therapeutic target for tumor-associated epileptic disorders.” In collaboration with the KAIST startup company, SoVarGen, the research team is currently developing innovative therapeutics for epileptic seizures derived from pediatric brain tumors. This study was supported by the Suh Kyungbae Foundation (SUHF) and the Citizens United for Research in Epilepsy. (Figure: Preoperative and postoperative brain MRI (left panel), tumor H&E (right upper panel) and GFAP immunohistochemical (right lower panel) staining images from a patient with ganglioglioma (GG231) carrying the BRAFV600E mutation. The white arrow and the black arrowhead indicate the brain tumor and a dysplastic neuron, respectively.)
Potential Drug to Cure Ciliopathies
(from left: Professor Joon Kim and PhD candidate Yong Joon Kim) Ciliopathies are rare disorders involving functional and structural abnormalities of cilia. Although they are rare, they may reach 1 in 1,000 births. Unfortunately, there are no small-molecule drugs for treating ciliary defects. A KAIST research team conducted successful research that introduces a potential treatment that will be a foundation for developing drugs to treat the disease as well as a platform for developing small-molecule drugs for similar genetic disorders. It was found that mutations in genes required for the formation or function of primary cilia cause ciliopathies and they result in cerebellar disorders, kidney dysfunction, and retinal degeneration. Primary cilia are cell organelles playing a crucial role in the human body. They participate in intercellular signal transduction during embryonic development and allow retinal photoreceptor cells to function. Currently, there are no approved drugs available for treating most ciliopathies. In fact, this is the case for most of the rare genetic disorders involving functional abnormalities through genetic mutation, and gene therapy is usually the only treatment available. To tackle this issue, a team led by Professor Joon Kim from the Graduate School of Medical Science and Engineering and Ho Jeong Kwon from Yonsei University constructed a cell that mimics a gene-mutated CEP290, one of the main causes of ciliopathies, through genome editing. They then used cell-based compound library screening to obtain a natural small-molecule compound capable of relieving defects in ciliogenesis, the production of cilia. The CEP290 protein forms a complex with a ciliopathy protein called NPHP5 to support the function of the ciliary transition zone. In cases where the CEP290 protein is not formed due to a genetic mutation, NPHP5 will not function normally. Here, the compound was confirmed to partially restore the function of the complex by normalizing the function of NPHP5. The team also identified that the compound is capable of retarding retinal degeneration by injecting the compound into animal models. As a result, they discovered a lead compound for developing medication to treat ciliopathy patients involving retinal degeneration. Hence, the findings imply that chemical compounds that target other proteins interacting with the disease protein can mitigate shortages of a disease protein in recessive genetic disorders. PhD candidate Yong Joon Kim stated, “This study shows how genetic disorders caused by genetic mutation can be treated with small-molecule drugs.” Professor Kim said, “Since the efficacy of the candidate drug has been verified through animal testing, a follow-up study will also be conducted to demonstrate the effect on humans.” This research was published in the Journal of Clinical Investigation on July 23. Figure 1. Identification of compounds that rescue ciliogenesis defects caused by CEP290 knockout Figure 2. Eupatilin injection ameliorates M-opsin trafficking and electrophysiological response of cone photoreceptors in rd16 mice
A Breakthrough for Understanding Glioblastoma: Origin Cells for Deadly Brain Tumors Identified
Figure 1. The pattern of GBM genesis is similar to that of firework. The bottom canon represents the first occurrence of the SVZ mutated cell. A new study by KAIST researchers identified where the mutation causing glioblastoma starts. According to the study, neural stem cells away from the tumor mass are the cells of origin that contain mutation drivers for glioblastoma, one of the most aggressive brain tumor. This breakthrough research, reported in Nature on August 1, gives insights for understanding why glioblastomas almost always grow back, even after surgery, and suggests novel ways to treat glioblastoma, which was previously thought to be incurable. Like most cancers, glioblastoma is treated with surgery to remove as much of the tumor as possible, then radiation and chemotherapy. However, it almost always returns in less than a year and its median survival time is only 15 months. Precision therapeutic approaches targeting tumors themselves didn’t lead to any breakthroughs. Professor Jeong Ho Lee’s team at the Graduate School of Medical Science and Engineering described direct genetic evidence through the deep sequencing of all triple-matched samples: normal SVZ tissue away from the tumor mass, tumor tissue, and normal cortical tissue. The research team studied 28 patients with glioblastomas and other types of brain tumors who underwent supra-total resection or other surgical resections of tumors, providing access to normal subventricular zone (SVZ) tissue (where neural stem cells are located) away from the tumor mass. The researchers used various deep and single cell sequencing technologies to conduct comparative DNA analysis on the samples from the patient’s SVZ tissue and tumors. They reported that normal SVZ tissue away from the tumor in 56.3% of patients with glioblastoma already contained low-level glioblastoma driver mutations that were observed at high levels in their matching tumors. Furthermore, the research team generated a genome edited mouse carrying glioblastoma mutations in the SVZ and showed that neural stem cells with mutations migrate from the SVZ lead to the development of glioblastomas in distant brain regions. (See the image below) Professor Lee conducted this study in collaboration with Professor Seok-Gu Kang of the Brain Tumor Center at Severance Hospital of Yonsei University. He said, “It’s easier to understand when we compare it to fireworks. Every flare flying around sky can be likened to cancer cells even though the fireworks are triggered on the ground. We found the trigger.” The identification of this mutation pathway of glioblastomas will lead to a new paradigm for therapeutic strategies. He added, “Now, we can focus on interrupting the recurrence and evolution of glioblastomas.” Professor Lee has investigated mutations arising in the brain for a decade. He is developing innovative diagnostics and therapeutics for untreatable brain disorders including intractable epilepsy and glioblastoma at a tech-startup, SoVarGen. “All technologies we used during the research were transferred to the company. This research gave us very good momentum to reach the next phase of our startup,” he remarked. Figure 2. Genetic analysis of tumor-free SVZ tissue and matching tumor tissue from GBM patients. Figure 3. Glioma progression in genome edited mice carrying GBM mutations in the SVZ
Mechanism Leading to Cortical Malformation from Brain-Only Mutations Identified
Focal malformations of cortical development (FMCDs) are a heterogeneous group of brain cortical abnormalities. These conditions are the most common causes of medically refractory epilepsy in children and are highly associated with intellectual disability, developmental delay, and autism-spectrum disorders. Despite a broad spectrum of cortical abnormalities in FMCDs, the defective migration of neuronal cells is considered a key pathological hallmark. A research team led by Professor Jeong Ho Lee in the Graduate School of Medical Science and Engineering at KAIST has recently investigated the molecular mechanism of defective neuronal migration in FMCDs. Their research results were published online in Neuron on June 21, 2018. The research team previously demonstrated that brain-only mutations in the mechanistic target of rapamycin (MTOR) gene causes focal cortical dysplasia, one major form of FMCDs leading to intractable epilepsy in children. However, the molecular mechanisms by which brain-only mutations in MTOR lead to cortical dyslamination and defective neuronal migration in FMCDs remain unclear. To study the molecular mechanism of brain cortical dyslamination, the research team utilized patients’ brain tissues and modeled the MTOR mutation-carrying cell and animal models recapitulating the pathogenesis and symptoms of FMCD patients. By performing comprehensive molecular genetic experiments, they found that the formation of primary cilia, one of cellular organelles, was disrupted in MTOR mutation-carrying neurons and demonstrated that this ciliary disruption was a cause of cortical dyslamination in FMCDs. MTOR mutations prevented degradation of the OFD1 protein, one of the negative regulators of ciliary formation. As a result, the OFD1 protein was abnormally accumulated in MTOR mutation-carrying neurons, causing focal cortical dyslamination. By suppressing the expression of the OFD1 protein, the research team was able to rescue the defective formation of primary cilia, leading to the restoration of cortical dyslamination and defective neuronal migration considerably. Based on these results, the research team is carrying out further research to develop novel therapeutics for patients with FMCDs caused by brain-only mutations. This work was supported by grants from the Suh Kyungbae Foundation and Citizens United for Research in Epilepsy. The research paper is titled “Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination.” (Digital Object Identifier #: 10.1016/j.neuron.2018.05.039) Picture 1: The disrupted formation of primary cilia in brain tissues of FMCD mouse models and patients with FMCDs caused by brain somatic mutations in MTOR. Picture 2: The rescue of defective ciliary formation in FMCD mouse models leading to the restoration of cortical dyslamination and defective neuronal migration.
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