TBK1

Funding Provided to 15 Academic Researchers from Across the US for New Innovations to Predict, Detect and Treat Brain Aneurysms HANOVER, Mass., Sept. 4, 2024 /PRNewswire/ -- The Brain Aneurysm Foundation (BAF), the leading advocacy organization supporting education, research, and policy to transform the treatment of brain aneurysms, today announced the recipients of its 2024 research grants. Grantees include leading academic researchers from across the United States, with the BAF recognizing 15 unique initiatives that include projects that use artificial intelligence to predict the likelihood of aneurysm formation, next-generation imaging to better detect and identify aneurysms, research on the potential use of embedded sensors and blood tests to predict ruptures, and projects focused on delivering better patient outcomes following a rupture. Continue Reading 2024 Brain Aneurysm Foundation Research Grant Recipients The researchers will be formally recognized at the BAF's 18th Annual Research Grant Symposium, which will be held in Boston on September 12. Awards of up to $50,000 will be provided to support each initiative. "I am very encouraged by the continued focus of our recipients on prevention and the use of tools such as AI and machine learning, as well as advanced imaging and biomarkers, to one day predict who is at increased risk of rupture so physicians can intervene before patients are impacted," said Dr. Christopher Ogilvy, M.D., Director of Endovascular and Operative Neurovascular Surgery at the Brain Aneurysm Institute at Beth Israel Deaconess Medical Center and a founder of the BAF. "Advances in device technology have transformed how we can address aneurysms once detected, but ultimately it is preventing ruptures that remains our paramount objective and where we need to focus our investment in innovation." Today, federal research funding for brain aneurysms is disproportionately small when compared to other neurological disorders and stroke, with just over two dollars committed to research for each person afflicted. The BAF is working with the National Institutes of Neurological Disorders and Stroke and Congress to close this imbalance as well as with researchers and academic institutions to expand their pursuit of NIH grants specific to brain aneurysms. "There is a growing appreciation amongst lawmakers for the need to increase research funding as they learn about the cost and prevalence of this disease and its long-term physical and economic impact on survivors, their families, and caregivers," said Christine Buckley, Executive Director of the BAF. "We believe today's pipeline of research and innovation can rapidly transform care for patients and significantly reduce the number of preventable deaths for the one in fifty people at risk. However, doing so requires increased engagement by all stakeholders across government, industry, and academia, and this is where our advocacy will continue to focus until we achieve this goal." This year's Research Grant symposium is being held in conjunction with the BAF's 30th anniversary, which will celebrate the organization's decades of advocacy as it furthers its mission to prevent brain aneurysms through educational programs for individuals and medical professionals to increase awareness of the signs and symptoms of a potential rupture, while providing resources and support for survivors, their families, and caregivers. 2024 BAF Research Grant Recipients: Umeshkumar Athiraman, MD, Washington University in St. Louis Targeting CCR6-CCL20 Axis for Improving Neurologic Outcomes After Subarachnoid Hemorrhage Holly Berns, MS, Northern Arizona University Utilizing Artificial Intelligence to Correlate Circle of Willis Morphology to Potential Aneurysm Formation Spiros Blackburn, MD, UTHealth, Houston Life Expectancy After Subarachnoid Hemorrhage: Damage vs Repair David Chung, MD, PhD, Massachusetts General Hospital Towards Real-Time Perfusion-Guided Management of Subarachnoid Hemorrhage Prajwal Ciryam, MD, PhD, University of Maryland A CSF Leukocyte Atlas to Predict Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage Robert Herbert, PhD, Louisiana State University Soft, Sensor-Embedded Cerebral Aneurysm Model Towards Predicting Rupture Risks Koji Hosaka, PhD, University of Florida, Gainesville Aneurysm Treatment and Healing: IL-17 Inhibition and Inflammatory Cascade Jennifer Kim, MD, PhD, Yale School of Medicine Leveraging EEG to Develop Comprehensive Automated DCI Prediction and Treatment Models Ioannis Koktzoglou, PhD, Endeavor Health Next-Generation Magnetic Resonance Angiography for Improved Structural and Hemodynamic Evaluation of Brain Aneurysms Takuma Maeda, MD, PhD, Barrow Neurological Institute The Effect of Novel Brain Penetrant Manganese Porphyrin-Based SOD Mimic on the Long-Term Outcomes of Subarachnoid Hemorrhage Farhad R. Nezami, PhD, Brigham and Women's Hospital, Boston AI-Driven Comprehensive Hemodynamic Analysis and Safety Prediction for Intracranial Aneurysm Flow Diversion Kamil Nowicki, MD, PhD and Adi Mittal, Columbia University and University of Pittsburgh A Blood Test to Detect Cerebral Aneurysms - Part II - Platform Development Tatsat Patel, PhD, University at Buffalo Generalizable Deep-Learning Algorithms for IA Management from Computed Tomography Angiography Imaging Yanning Rui, PhD, UTHealth, Houston Treating Intracranial Aneurysms by Targeting TBK1-Mediated Endothelial FA-Phagy Scott Simon, MD, The Pennsylvania State University Understanding How Genetic Variations in the Metabolism of Iron Impacts Recovery from Subarachnoid Hemorrhage About the Brain Aneurysm Foundation Based in Hanover, Massachusetts, the Brain Aneurysm Foundation is the globally recognized leader in brain aneurysm awareness, education, support, advocacy, and research funding. The foundation's mission is to provide information about and raise awareness of the symptoms and risk factors of brain aneurysms to prevent ruptures and subsequent death and disability; work with medical communities to provide support networks for patients and families; and advance research to improve patients' outcomes and save lives. Established in 1994, the foundation has a Medical Advisory Board that comprises more than 40 of the world's foremost aneurysm experts — neurologists, neurosurgeons, interventional neuroradiologists, and other brain aneurysm specialists — from leading hospitals and universities. For more information about the Brain Aneurysm Foundation, please visit bafound.org or follow us on Facebook, Twitter, LinkedIn, Instagram and YouTube. Media Contact: Lynn Nuttall Director of Marketing and Communications Brain Aneurysm Foundation 781-826-5556 x 208 [email protected] bafound.org SOURCE Brain Aneurysm Foundation

- Oral and poster presentations show novel, differentiated properties optimized to progress company’s nomination of lead development candidate for the treatment of autoimmune diseases - - FOCIS recognizes Exo with 2024 Annual Meeting Award for exceptional research and posters of merit - CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Exo Therapeutics, Inc., a company developing a pipeline of drug candidates that target exosites, unique small-molecule binding pockets that are distal to traditional active and allosteric sites, thereby reprogramming enzyme activity for precise and robust therapeutic effect, today presented a poster and oral presentation on its preclinical program targeting TBK1/STING interaction of the cGAS-STING pathway at the 24th Annual Meeting of the Federation of Clinical Immunology Societies (FOCIS 2024) in San Francisco. Data presented in both the poster and oral presentation show that the company has identified potent, selective exosite-targeted TBK1/STING inhibitors, demonstrated efficacy across preclinical models and optimized properties towards development candidate nomination. FOCIS also recognized Exo with the 2024 Annual Meeting Award for exceptional research and posters of merit for the Company’s poster and oral presentation. “Exo’s data look very promising, particularly the targeting of both interferon-beta and NF-kB pathways by your molecule,” said Mary K. Crow, M.D., Physician-in-Chief Emeritus at Hospital for Special Surgery and Professor of Medicine at Weill Cornell Medical College. “There is a great need to define the role of the TBK1/STING pathway in Systemic Lupus Erythematosus (SLE) and other autoimmune diseases. I hope Exo’s development program can soon move forward into patients with their interesting drug!” Exo’s goal is to expand the druggable universe with exosite-specific molecules that enable a new, tailored way to target and reprogram enzymes. Historically, active-site inhibitors have failed because of inadequate selectivity of their inhibitory activity, leading to off-target effects and poor therapeutic indices. Moreover, molecules focused on active or allosteric sites typically inhibit the full functionality of proteins, which can direct both beneficial and harmful effects. In contrast, TBK1/STING exosite inhibitors have the promise of mitigating the unwanted effects while providing therapeutic benefit. The presentations detailed Exo’s novel TBK1 exosite inhibitors that disrupt recruitment by STING for downstream activation of type-1 interferon and NF-κB responses. More specifically, TBK1 exosite inhibitors selectively inhibit the TBK1-STING axis while sparing non-disease relevant housekeeping functions of the kinase, which will be more likely to offer superior efficacy and an improved therapeutic window versus traditional approaches. The company also shared findings from rational and structure-based drug discovery efforts that demonstrated identification of a series of selective TBK1 exosite inhibitors with potent binding affinities that translate into nanomolar inhibition of IFNβ in THP1 cells and primary human cell types. Additionally, orally bioavailable TBK1 exosite inhibitors were evaluated in both in vivo and ex vivo models to inhibit proximal and distal pharmacodynamic markers upon stimulation with a STING agonist. Treatment with TBK1 exosite inhibitors caused a dramatic reduction of pro-inflammatory cytokines including IFNβ, CXCL-10, CXCL-9 and IFIT1 in a pathway-driven model, the TREX-1 null mouse. Additionally, Exo’s TBK1 exosite inhibitors have shown robust effects in SLE and Scleroderma patient samples. Most notably, when assessed for activity in SLE patient-derived human whole blood and PBMC, TBK1 exosite inhibitors robustly suppressed pathway activation. Similarly, upon activation of cGAS-STING-TBK1 pathway, TBK1 exosite inhibitors inhibited cytokine production in disease-relevant skin inflammatory models, fibroblasts and keratinocytes. Poster Details Title: A Novel Inhibitor of cGAS-STING-TBK1 Pathway with Broad Application in Autoimmune Diseases Date: Wednesday, June 19, 2024, 7:30 AM - 7:30 PM Poster Number: W102 Location: San Francisco Marriott Marquis – Salon 9, Lower B2 Level Oral Presentation Details Title: A Novel Inhibitor of cGAS-STING-TBK1 Pathway with Broad Application in Autoimmune Diseases Date: Wednesday, June 19, 2024, 4:15 PM - 4:30 PM Presenter: Bhavatarini Vangamudi, Ph.D. About Exo Therapeutics Exo Therapeutics is a small molecule drug discovery and development company co-founded by Professors David R. Liu, Alan Saghatelian, and Juan Pablo Maianti with a pioneering technology to address intractable pharmaceutical targets. By leveraging the company’s ExoSight™ platform, Exo is developing a deep pipeline of potent drug candidates that bind exosites, distal and unique binding pockets that have the potential to reprogram enzyme activity for precise and robust therapeutic effect. Through this specific and selective approach to challenging targets, the company's team of world-class researchers is unlocking breakthrough therapeutics in inflammation, oncology and a broad range of other diseases. For more information, visit .

Researchers uncovered the mechanistic details behind how several proteins interact to help cells recognize and remove damaged mitochondria. Optineurin (OPTN) and its interactions are needed to provide a contact site for another protein, Tank-binding kinase 1 (TBK1), during this process. The OPTN-TBK1 relationship is necessary for these mitochondria to be recognized and eliminated from the cell. This mechanism may have relevance for developing drugs to treat Parkinson's disease. Autophagy is a process used by cells as a recycling system to transport and break down organelles and other cytosolic components, which become enveloped in a membrane called the autophagosome (Fig 1). When this involves the removal of damaged mitochondria, commonly called the "powerhouse" of the cell, it is known as mitophagy. In a recent article published in The EMBO Journal, a team led by researchers at Tokyo Medical and Dental University (TMDU) elucidated the molecular details of how an enzyme called Tank-binding kinase 1 (TBK1) participates in a disease-relevant mitophagy mechanism. Although autophagy has been characterized as a more general process meant to degrade and clear various cellular components, recent data have suggested that certain pathways are specifically involved in the autophagy of particular organelle types that are damaged or no longer needed. The researchers became interested in mitophagy mediated by molecules called PINK1 and Parkin, as they are proteins that have been pathologically linked to Parkinson's disease. "Mitophagy-related defects have been directly implicated in the neurodegeneration observed in Parkinson's disease patients," says Koji Yamano, lead author of the study. "Normally, PINK1 and Parkin work together to mark damaged mitochondria for removal by adding a chain of molecules called ubiquitin. This mark allows proteins called autophagy adaptors to associate with the mitochondria and bring in the autophagy machinery for autophagosome development." Although TBK1 is known to participate in PINK1/Parkin-mediated mitophagy, a detailed mechanism how it activates remained unclear. Using various molecular biology techniques, the team found that deleting the gene encoding TBK1 prevented association of an autophagy adaptor called optineurin (OPTN) during Parkin-mediated mitophagy (Fig 2). Additionally, deleting the OPTN gene prevented autophosphorylation of TBK1, which is necessary for it to function. Further work suggested that the interactions between OPTN and ubiquitin, as well as between OPTN and the developing autophagosome, were all needed for OPTN and TBK1 to come together at the contact site between damaged mitochondria and the pre-autophagosome membrane. Without this contact site, TBK1 autophosphorylation could not occur. The researchers also generated molecules called monobodies in their lab that could specifically bind OPTN and inhibit its physical interactions. The monobodies prevented OPTN accumulation at the mitophagy contact sites (Fig 3A). This subsequently blocked TBK1 activation (Fig 3B) and thereby mitochondrial degradation. These experiments further emphasized the importance of the OPTN-TBK1 relationship to support proper mitophagy. "Because PINK1 and Parkin are critical contributors to the molecular basis of Parkinson's disease, understanding the mechanistic details related to the mitophagy process mediated by these molecules is very important," explains Yamano. This study demonstrates a positive and reciprocal relationship between OPTN and TBK1 that is necessary for autophagosomes to begin forming on damaged mitochondria. The impactful finding may lead to the development of novel drugs to treat Parkinson's disease.