fibrin

- THN391 demonstrated effectiveness in protecting against vascular and neuronal degeneration - - Therini Bio plans to initiate a Phase 1/2a trial evaluating THN391 in DME in 2H24 - - The data was presented at ARVO 2024 - SACRAMENTO, Calif., May 08, 2024 (GLOBE NEWSWIRE) -- Therini Bio, Inc., a clinical-stage biotech company developing fibrin-targeting immunotherapies for neurodegenerative diseases driven by vascular dysfunction, today announced positive preclinical data supporting the development of its lead candidate, THN391, for the treatment of neurodegenerative ocular diseases. The data was detailed in a poster presented by Aaron Kantor, Ph.D., Head of Translational Sciences at Therini Bio, at the Association for Research in Vision and Ophthalmology (ARVO) 2024 Annual Meeting in Seattle, WA, on May 7, 2024. Vascular dysfunction, caused by factors such as aging, genetic risk and diseases, including hypertension and diabetes, leads to the toxic accumulation of fibrin deposits outside of blood vessels, which sparks chronic innate immune cell activation and is believed to be a central mechanism underlying many neurodegenerative ocular diseases, including diabetic retinopathy (DR), diabetic macular edema (DME) and age-related macular degeneration (AMD). Therini Bio has developed a potential first-in-class therapeutic monoclonal antibody, THN391, that is designed to selectively block fibrin-mediated neuroinflammation without interfering with fibrin’s coagulation properties. In preclinical models of macular degeneration and diabetic retinopathy, THN391 and its analogs demonstrated effectiveness in protecting against vascular and neuronal degeneration. In a rat laser-induced choroidal neovascularization (LCNV) model of macular degeneration, intravitreal injection of THN391 significantly reduced both lesion area and permeability as measured by quantitative fluorescein angiography (qFA). THN391’s treatment effect was comparable to the reduction exhibited by VEGF antagonists. Results were directionally similar in a mouse STZ (streptozotocin) model of diabetic retinopathy, with THN391 reducing vascular permeability, as measured by qFA. “We are very encouraged by our data demonstrating the effectiveness of THN391 in rodent models of neurodegenerative ocular diseases,” said Joel Naor, M.D., Chief Medical Officer - Ophthalmology at Therini Bio. “Our research indicates that THN391 as monotherapy, or in combination with VEGF-antagonists, has the potential to positively impact key disease mechanisms propagated by macrophages and provide patients with benefits beyond standard of care.” Therini Bio plans to initiate a Phase 1/2a study assessing THN391 for the treatment of DME in 2H24, in preparation for testing a novel fibrin/VEGF bispecific antibody. An interim readout of an ongoing Phase 1a study in healthy volunteers found intravenous THN391 to be safe, well-tolerated, have an extended half-life and no negative impact on coagulation. Presentation Details: Session: AMD: Translational StudiesTitle: A Novel Anti-Fibrin Antibody to Treat Neurogenerative Ocular DiseasesPoster Number: B0453Abstract Number: 3790 – B0453Presenter: Aaron Kantor, Ph.D., Head of Translational Sciences at Therini Bio The poster is available in the Publications section of www.therinibio.com. About Therini Bio, Inc. Therini Bio is a clinical-stage biotech company developing immunotherapies for neuroinflammation in diseases driven by vascular dysfunction. The Company is developing a pipeline of potential first-in-class therapies selectively targeting toxic fibrin accumulation for diseases, including Alzheimer’s disease (AD) and Diabetic Macular Edema (DME), where destructive neuroinflammation plays a central role in the disease process. The foundational science was licensed based on technology discovered in Katerina Akassoglou’s, Ph.D., laboratories at the Gladstone Institutes at the University of California San Francisco (UCSF) and formerly the University of California San Diego (UCSD). Therini Bio’s top-tier syndicate of life sciences investors includes the Alzheimer’s Drug Discovery Foundation, SV Health Investors’ Biotech Fund and Dementia Discovery Fund, Dolby Family Ventures, Dreavent Biotech Investments, Eli Lilly and Company, Foundation for a Better World, MRL Ventures Fund, the therapeutics-focused corporate venture fund of Merck & Co., Inc., and Sanofi Ventures. For more information, visit www.therinibio.com. Contact Tara Nickerson, Ph.D.Chief Executive Officertnickerson@therinibio.com

Research from Gladstone Institutes reveals that a blood coagulation protein is responsible for initiating toxic inflammation and neuron loss after a major head injury. The findings can inform new treatment strategies for a condition that often presents long-term health challenges. SAN FRANCISCO, April 19, 2024 /PRNewswire/ -- For the roughly 1.5 million Americans per year who survive a traumatic brain injury, health outcomes vary widely. Not only can these injuries lead to a loss of coordination, depression, impulsivity, and difficulty concentrating, but they come with an amplified risk for developing dementia in the future. Continue Reading Jae Kyu Ryu, left, and Zhaoqi Yan, right, collaborate in the Gladstone lab of Katerina Akassoglou. Using three-dimensional imaging technology, the Gladstone team examined blood-brain barrier leaks and distribution of the blood-clotting protein fibrin in a whole intact mouse brain after traumatic brain injury. Fibrin deposits appear in red. The glaring absence of treatments for such a widespread condition drove a team of scientists at Gladstone Institutes to uncover, on a molecular level, how traumatic brain injuries trigger neurodegeneration—and just as importantly, how to target that process to prevent long-term damage. "We set out to address the fundamental question of exactly what happens in the brain after injury to ignite the damaging process that destroys neurons," says Jae Kyu Ryu, PhD, a scientific program leader in the lab of Katerina Akassoglou, PhD, at Gladstone Institutes. Most traumatic brain injuries come as a result of falls, car crashes, or violent assaults, according to the Centers for Disease Control, but many also stem from sports accidents or certain military operations such as explosions. In each case, the external force is strong enough to move the brain within the skull, causing a significant breakdown in the blood-brain barrier and allowing blood to move in. "We knew that a specific blood protein, fibrin, was present in the brain after traumatic brain injury, but we didn't know until now that it plays a causative role in brain damage after injury," says Ryu, who led the study that appears in the Journal of Neuroinflammation. Ryu and others in Akassoglou's lab have long investigated how blood that leaks into the brain triggers neurologic diseases, essentially by hijacking the brain's immune system and setting off a cascade of harmful, often-irreversible effects. Fibrin, a protein that normally helps blood coagulate, is the culprit. "Across many neurological diseases, toxic immune responses in the brain are triggered by blood leaks and drive neurodegeneration," says Akassoglou, a senior investigator at Gladstone and the director of the Center for Neurovascular Brain Immunology at Gladstone and UC San Francisco. "Neutralizing the toxic immune responses in the brain paves the way to new therapies for neurological diseases." In diseases such as Alzheimer's and multiple sclerosis, abnormal leaks in the protective blood-brain barrier allow fibrin to seep into areas responsible for cognitive and motor functions causing neurodegeneration. But in this case, the traumatic brain injury itself causes the blood to leak into the brain. The new study showed, for the first time, that fibrin is responsible for turning good immune cells bad, causing dangerous inflammation and unleashing toxins that kill neurons. The Gladstone team used state-of-the-art imaging technology to study mouse brains, as well as brains from people who experienced a traumatic brain injury. They also produced three-dimensional imaging of a whole intact mouse brain, showing blood-brain barrier leaks and abundant fibrin in traumatic brain injury. In both mouse and human brains, fibrin was present together with activated immune cells. "It became clear that fibrin is activating these immune cells," Ryu says. "We realized that we can prevent the toxic effects if we could block fibrin, but we had to do it in a precise way." The team leveraged genetic tools with a specific mutation in fibrin that can block it from activating immune cells without affecting the protein's beneficial blood-clotting abilities. This is especially critical for traumatic brain injuries, as excessive bleeding into the brain has been known to occur among patients who were taking anticoagulant medications before their injury. Akassoglou's lab previously developed a drug, a therapeutic monoclonal antibody, that acts only on fibrin's inflammatory properties, without adverse effects on blood coagulation. This fibrin-targeting immunotherapy protects from multiple sclerosis and Alzheimer's disease in mice. A humanized version of this first-in-class fibrin immunotherapy is already in Phase 1 safety clinical trials by Therini Bio. "It's exciting to have a therapeutic option to neutralize blood toxicity in neurologic diseases," Ryu says. "Future studies are needed to test the effects of the fibrin immunotherapy in traumatic brain injury." "This study identifies a potential new strategy to diminish the devastating impacts of brain injuries," says Lennart Mucke, MD, director of the Gladstone Institute of Neurological Disease. "Brain injuries can have profound effects on a person's cognitive abilities, emotional health, and motor skills, touching every part of their life. It will be interesting to explore whether blocking the disease-promoting effects of fibrin can improve the outcome of brain surgeries and reduce disability when implemented after traumatic brain injuries have occurred." About the Study The study, "Fibrin promotes oxidative stress and neuronal loss in traumatic brain injury via innate immune activation," appears in the April 15, 2024, issue of Journal of Neuroinflammation. Authors include Terry Dean, Andrew Mendiola, Zhaoqi Yan, Rosa Meza Acevedo, Belinda Cabriga, Katerina Akassoglou, and Jae Kyu Ryu. The work was supported by the National Institutes of Health, the Thrasher Research Fund Early Career Award, the National Multiple Sclerosis Society, the Kaganov Scholarship for Excellence in Neuroscience, the Conrad N. Hilton Foundation, the Dolby Family, 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. Media Contact Kelly Quigley Gladstone Institutes Director of Science Communications and Media Relations [email protected] SOURCE Gladstone Institutes

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.