fibrin

A new type of synthetic heart valve could soon be available to help treat children living with chronic rheumatic heart disease. Researchers at Harvard University’s Wyss Institute and John A. Paulson School of Engineering and Applied Sciences (SEAS) are reportedly closer to releasing their FibraValve, a next-generation implantable heart valve that is anticipated to reduce the number of invasive surgeries typically required for kids growing up with pediatric heart valve disease. The condition typically affects older individuals but it can also be congenital or brought on by infections such as strep throat when treatment is not ideal. The spun-fiber valve can be manufactured in less than 10 minutes by utilizing a new method known as focused rotary jet spinning (FRJS), a process that allows the valve’s delicate flaps to have customizable shapes and properties down to the nanoscale. According to a recent study published in the peer-reviewed journal Matter , FibraValve was readily colonized by living cells in vitro and in large animal model studies conducted by collaborators led by the Wyss Zurich Translational Center in Switzerland. “This study illustrates FibraValve’s potential as a solution for children suffering from valve diseases,” said Kit Parker, PhD, associate faculty member at the Wyss Institute and the Tarr Family Professor of Bioengineering and Applied Physics at SEAS, in a press release issued by Wyss Institute officials. “Our goal is for the patient’s native cells to use the device as a blueprint to regenerate their own living valve tissue, but FRJS also has potential as a platform to fabricate other medical devices in the future.” The jet (spinning) set A follow-up to the institute’s first synthetic heart valve — the JetValve , the first device manufactured using the nanofiber fabrication technique FRJS — FibraValve has been in development since 2014, according to Wyss officials. The FRJS technique extrudes a biocompatible synthetic polymer solution into long fibers that wrap themselves around a mandrel shaped like a heart valve. As Wyss officials describe it, the FRJS process is similar to how a cotton candy machine spins sugar crystals into the fluffy substance that’s wrapped around a paper cone. Image courtesy of Wyss Institute at Harvard University Focused rotary jet spinning produces long fibers from a biocompatible synthetic polymer solution that wrap themselves around a mandrel. The process can be be compared to a cotton candy machine. The JetValve previously has been successfully implanted into a sheep’s heart using minimally invasive surgery, recruiting living cells to regenerate new tissue on the device. Building on this approach, researchers have reportedly re-visited multiple aspects of JetValve manufacturing, fiber material, and geometric design as they have worked on the FibraValve. Polymer fibers mimic heart valve's tissue structure For the manufacturing process, streams of focused air are added to the polymer-extruding stream to create FRJS. This has allowed for improvements in the rate that polymer fibers are deposited onto the mandrel and in the ability to adjust the resulting valve to a final desired shape. The polymer also produces networks of microfibers and nanofibers that better mimic the tissue structure of a human heart valve. A newly customized polymer material known as PLCL has also been used to improve the infiltration of living cells once the FibraValve is implanted. A combination of polycaprolactone (PCL) and polylactic acid (PLA), PLCL has been shown in previous studies to last approximately six months after implantation in rats. According to Wyss officials, PLCL is infiltrated by living cells, remodeled into functional tissue, and is safely biodegradable. FibraValve reportedly also enables a more even distribution of cells throughout its scaffold than valves made of other polymers. The geometry of the FibraValve is said to be optimized through the shape of the valve’s inner “leaflets” to minimize leakage of blood backwards through the valve. Use of the valve reportedly reduced the amount of leakage from ~30% with the JetValve to ~13% with the newly designed FibraValve. Recent results, future testing After implantation into a living sheep’s heart using minimally invasive surgery, FibraValve reportedly began to function immediately, with red and white blood cells infiltrating the valve’s porous scaffolding, and fibrin protein being deposited on the outside of the valve, within one hour. The valve also displayed no damage or problems following implantation. Longer-term animal testing to evaluate FibraValve’s performance and regenerative capabilities over weeks and months is anticipated to occur soon. Other potential implantable devices with FRJS could also include cardiac patches and blood vessels. “This approach to heart valve replacement might open the door toward customized medical implants that regenerate and grow with the patient, making children’s lives better,” said Michael Peters, co-first author of the recent study and a graduate student at the Wyss Institute and SEAS.

New research into how blood makes the brain's immune cells toxic points to new treatments for Alzheimer's disease and multiple sclerosis SAN FRANCISCO, June 8, 2023 /PRNewswire/ -- In patients with neurological diseases like Alzheimer's disease and multiple sclerosis, immune cells in the brain known as microglia that normally fulfill beneficial functions become harmful to neurons, leading to cognitive dysfunction and motor impairment. These harmful immune cells may also contribute to age-related cognitive decline in people without dementia. For some time, scientists have been trying to better understand the triggers responsible for turning good microglia bad, and their exact contribution during disease. If they could identify what makes microglia toxic, they could find new ways to treat neurological diseases. Now, researchers at Gladstone Institutes led by Senior Investigator Katerina Akassoglou, PhD, showed that exposure to blood leaking into the brain turns on harmful genes in microglia, transforming them into toxic cells that can destroy neurons. The scientists discovered that a blood protein called fibrin—which normally aids blood clotting—is responsible for turning on the detrimental genes in microglia, both in Alzheimer's disease and multiple sclerosis. The findings, published in the journal Nature Immunology, suggest that counteracting the blood toxicity caused by fibrin can protect the brain from harmful inflammation and loss of neurons in neurological diseases. "Our study answers, for the first time in a comprehensive way, how blood that leaks into the brain hijacks the brain's immune system to cause toxic effects in brain diseases," says Akassoglou, who is also director of the Center for Neurovascular Brain Immunology at Gladstone and a professor of neurology at UC San Francisco (UCSF). "Knowing how blood affects the brain could help us develop innovative treatments for neurological diseases." Specific Effects of Blood Proteins Individuals with neurological diseases like Alzheimer's disease and multiple sclerosis have abnormalities within the vast network of blood vessels in their brain, which allow blood proteins to seep into brain areas responsible for cognitive and motor functions. Blood leaks in the brain occur early and correlate with worse prognosis in many of these diseases. To understand which proteins in the blood affect gene and protein changes in immune cells, Akassoglou and her team took a systematic approach to determine how losing key blood proteins—such as albumin, complement, and fibrin—would affect immune cells in mice. They analyzed the effect of the blood proteins with a suite of advanced molecular and computational technologies in collaboration with Nevan Krogan, PhD, senior investigator at Gladstone and director of the Quantitative Biosciences Institute at UCSF, and Alex Pico, PhD, research investigator and director of the Bioinformatics Core at Gladstone. In the new study, the researchers found that different blood proteins activate distinct molecular processes in microglia. What's more, they identified that fibrin is responsible for driving unique gene and protein activities that make microglia toxic to neurons. The other blood proteins tested were not mainly responsible for these toxic effects. "We combined cutting-edge tools to capture a broad view of all the microglia processes triggered by distinct blood proteins," says Andrew Mendiola, PhD, a scientist in Akassoglou's lab and first author of the study. "Fibrin stood out, as it triggered a dramatic gene response in microglia, which mirrored gene signatures identified in chronic neurological diseases such as Alzheimer's disease." In prior research, Akassoglou and her team had discovered that fibrin can activate microglia and promote cognitive impairment in mice. Indeed, the researchers were able to narrow down fibrin's bad influence to a specific inflammatory region of the protein. This region does not impact fibrin's critical role in blood clotting. In the new study, the team showed that removing that inflammatory region reduced fibrin's ability to turn on toxic genes in microglia, and restored the protective functions of these immune cells. Implications for Neurological Diseases and Therapies To assess whether their findings are relevant to disease, the researchers used a technique they developed to identify toxic gene activities in cells in mouse models of Alzheimer's disease and of multiple sclerosis. In both types of models, fibrin activated microglia genes involved in neurodegeneration and oxidative stress, processes that have been linked to both Alzheimer's disease and multiple sclerosis. "We think that, across neurological diseases, fibrin deposits at sites of blood leaks might drive toxic immune responses," Mendiola says. "Identifying approaches to selectively inhibit these toxic responses could be a game changer for treating disease." Akassoglou's lab has already developed one such drug, a therapeutic monoclonal antibody against fibrin's inflammatory domain. The antibody blocks the detrimental effects of fibrin without adverse effects on blood clotting, and protects from multiple sclerosis and Alzheimer's disease in mice. A humanized version of this first-in-class fibrin immunotherapy has now started Phase 1 safety clinical trials. "Neutralizing blood toxicity could protect the brain from harmful inflammation and restore neuronal connections required for cognitive functions," says Akassoglou. "By targeting fibrin, we can block toxic microglia cells without affecting their protective functions in the brain." The study generated a large amount of molecular data that is now freely available for other researchers to use. The open-access atlas of how the blood affects the brain could be further analyzed to reveal other functions of blood proteins and support the discovery of new drugs and biomarkers. "These exciting findings change the way we think about blood proteins, from secondary bystanders to primary drivers of harm in the brain," says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease. "The mechanisms identified in this study could be at work in a range of neurological conditions involving blood leaks in the brain, including neurodegenerative disorders, autoimmune diseases, stroke, and traumatic brain injury. Therefore, they have far-reaching therapeutic implications." About the Study The paper "Defining blood-induced microglia functions in neurodegeneration through multiomic profiling" was published in the journal Nature Immunology on June 8, 2023. Other authors are Zhaoqi Yan, Karuna Dixit, Jeffrey Johnson, Anke Meyer-Franke, Min-Gyoung Shin, Yu Yong, Ayushi Agrawal, Eilidh MacDonald, Gayathri Muthukumar, Clairice Pearce, Nikhita Arun, Belinda Cabriga, Rosa Meza-Acevedo, Maria del Pilar S. Alzamora, and Jae Kyu Ryu of Gladstone; and Mehdi Bouhaddou and Scott Zamvil of UCSF. The work was supported by the National Institutes of Health (C06 RR018928, T32 AI007334, K99 NS126707, RF1 AG064926, R35 NS097976), the National Multiple Sclerosis Society (FG-1708-28925), the Berkelhammer Award for Excellence in Neuroscience, the BrightFocus Foundation (A2021019F), the Conrad N. Hilton Foundation (17348), the Ray and Dagmar Dolby Family Fund, Edward and Pearl Fein, and the Simon Family Trust. About Gladstone Institutes Gladstone Institutes is an independent, nonprofit life science research organization that uses visionary science and technology to overcome disease. Established in 1979, it is located in the epicenter of biomedical and technological innovation, in the Mission Bay neighborhood of San Francisco. Gladstone has created a research model that disrupts how science is done, funds big ideas, and attracts the brightest minds. 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- Industry Veteran Frank D. Lee Appointed as Executive Chairperson of the Board SOUTH SAN FRANCISCO, Calif.--(BUSINESS WIRE)-- Therini Bio, Inc., a biotech company focused on developing fibrin-targeted therapies to treat inflammatory neurodegenerative and retinal diseases, today announced the initiation of first-in-human dosing for a Phase 1 trial of its lead asset THN391, a fibrin-targeting therapeutic candidate for Alzheimer’s disease. THN391 binds to the inflammation-driving component of fibrin that is known to activate pathological immune responses in neurodegenerative and ophthalmologic diseases. Importantly, based on preclinical studies to date, targeting this region does not impact or diminish fibrin’s critical role in blood clotting and coagulation. Key safety and proof of mechanism clinical data is expected by the end of 2024. “Initiating first-in-human dosing for THN391 is a significant milestone and we’re excited about the approach that Therini Bio is taking towards treating Alzheimer’s disease and other inflammatory neurodegenerative and retinal diseases. As an early investor in Therini, we look forward to continue supporting the Company’s mission of developing potential first-in-class therapies targeting toxic fibrin accumulation for areas of significant unmet patient need,” said Laurence Barker, Partner, Dementia Discovery Fund (DDF). As Therini Bio enters a new era of growth as a clinical-stage company, it has appointed industry veteran Frank D. Lee as Executive Chairperson of the Board at Therini Bio. Frank was most recently President and CEO of Forma Therapeutics until its acquisition by Novo Nordisk for $1.1B in 2022. He brings over 25 years’ global experience in product development and commercial leadership across a wide range of therapeutic areas within the biotech and pharmaceutical industry. He was also Senior Vice President, Global Product Strategy and Therapeutic Area Head for the Immunology, Ophthalmology and Infectious Diseases at Genentech, a member of the Roche Group, where he was responsible for driving development and commercial strategy for a broad portfolio of molecules in development and for global in-line product sales of more than $11B. Frank’s 13-year career path at Genentech included leadership positions of increasing scope and responsibility for delivering transformative medicines to patients. Prior to joining Genentech, Frank spent approximately 13 years across Novartis, Janssen and Eli Lilly in engineering, manufacturing, sales/marketing and business development. Frank received a bachelor’s degree in Chemical Engineering from Vanderbilt University and an MBA in marketing and finance from the Wharton Graduate School of Business. He currently serves as chair of the board of Catamaran Bio and as an independent board member of Bolt Bio. He previously served on the board of directors of the Genentech Foundation. "We are thrilled to announce the initiation of first-in-human dosing for THN391, our fibrin-targeting therapeutic candidate for Alzheimer's disease. This is a major milestone for the Company, and as part of our continued growth, we are excited to welcome Frank as Executive Chairperson of the Board at Therini Bio. Frank's extensive experience in product development and commercial leadership will be invaluable as we enter this new era as a clinical-stage company," said Michael Quigley, Ph.D., President and CEO of Therini Bio. "I am honored to be joining Therini Bio as Executive Chairperson of the Board, as the Company advances its first clinical candidate THN391 as a fibrin-targeting therapeutic candidate for Alzheimer's disease,” said Frank D. Lee, Executive Chairperson of the Board, Therini Bio. “I look forward to working alongside the Therini Bio team to help advance this candidate and its pipeline of fibrin-targeted therapeutic candidates. Therini Bio has assembled a talented group of experienced pharma and biotech veterans with a deep commitment to improving patient outcomes, and I am thrilled to be a part of this effort." “Sanofi Ventures is passionate about supporting innovative companies that are developing breakthrough therapies for patients in need. We are thrilled to have Frank join Therini Bio as Executive Chairperson of the Board, as Therini Bio advances their fibrin-targeting therapeutic candidate for Alzheimer's disease and retinal diseases. We look forward to working with the team throughout development in multiple indications,” said Laia Crespo, Partner, Sanofi Ventures. About Therini Bio, Inc. Therini Bio is a biotech company focused on developing fibrin-targeted therapies to treat inflammatory neurodegenerative and retinal diseases. The Company is developing a pipeline of potential first-in-class therapies targeting toxic fibrin accumulation, for diseases including Alzheimer's disease (AD), multiple sclerosis (MS), as well as in a variety of retinal diseases, such as diabetic macular edema (DME) where destructive inflammation plays a role in the disease process. The foundational science was licensed based on technology discovered in Katerina Akassoglou, Ph.D. laboratories at the Gladstone Institutes at the University of California San Francisco (UCSF) and formerly the University of California San Diego (UCSD). For more information, visit .