HDAC3

Scientists have identified a new therapeutic approach for combating neurodegenerative diseases, offering hope of improved treatments for Alzheimer's disease, Parkinson's disease, Vanishing White Matter disease and multiple sclerosis, among others. A team led by scientists at the Case Western Reserve University School of Medicine has identified a new therapeutic approach for combating neurodegenerative diseases, offering hope of improved treatments for Alzheimer's disease, Parkinson's disease, Vanishing White Matter disease and multiple sclerosis, among others. Neurodegenerative diseases, which affect millions of people worldwide, occur when nerve cells in the brain or nervous system lose function over time and ultimately die, according to the National Institutes of Health. Alzheimer's disease and Parkinson's disease are the most common. The research team's new study, published online February 20 in the journal Nature Neuroscience, focused on astrocytes -- the brain's most abundant cells, which normally support healthy brain function. Growing evidence indicates astrocytes can switch to a harmful state that increases nerve-cell loss in neurodegenerative diseases. The researchers created a new cellular technique to test thousands of possible medications for their ability to prevent these rogue astrocytes from forming. "By harnessing the power of high-throughput drug-screening, we've identified a key protein regulator that, when inhibited, can prevent the formation of harmful astrocytes," said Benjamin Clayton, lead author and National Multiple Sclerosis Society career transition fellow in the laboratory of Paul Tesar at the Case Western Reserve School of Medicine. They found that blocking the activity of a particular protein, HDAC3, may prevent the development of dangerous astrocytes. The scientists discovered that by administering medications that specifically target HDAC3, they were able to prevent the development of dangerous astrocytes and significantly increase the survival of nerve cells in mouse models. "This research establishes a platform for discovering therapies to control diseased astrocytes and highlights the therapeutic potential of regulating astrocyte states to treat neurodegenerative diseases," said Tesar, the Dr. Donald and Ruth Weber Goodman Professor of Innovative Therapeutics and the study's principal investigator. Tesar, also director of the School of Medicine's Institute for Glial Sciences, said more research needs to be done before patients might benefit from the promising approach. But, he said, their findings could lead to the creation of novel therapies that disarm harmful astrocytes and support neuroprotection -- perhaps improving the lives of people with neurodegenerative illnesses in the future. "Therapies for neurodegenerative disease typically target the nerve cells directly," Tesar said, "but here we asked if fixing the damaging effects of astrocytes could provide therapeutic benefit. Our findings redefine the landscape of neurodegenerative disease treatment and open the door to a new era of astrocyte targeting medicines." The team included additional researchers from the Case Western Reserve School of Medicine, and from the George Washington School of Medicine, The Ohio State University and the University of Tampa. The research was supported by grants from the National Institutes of Health, National Multiple Sclerosis Society and Hartwell Foundation, and philanthropic support by sTF5 Care and the R. Blane & Claudia Walter, Long, Goodman, Geller and Weidenthal families.

Eye-opening research from experts at Cincinnati Children's suggests it's possible CINCINNATI, Jan. 30, 2024 /PRNewswire/ -- Imagine a day when people can enjoy snacking on foods designed to "re-calibrate" their microbiomes—that vast population of friendly bacteria living in our intestines—in order to promote a healthy immune system and decrease infections or chronic inflammation. Continue Reading What are tuft cells? This confocal microscope image shows that projections extending into the lumen of the intestine are lined by epithelial cells (magenta) that arise from stem cells located at the base of these projections. Tuft cells (yellow) are a unique type of epithelial cell that regulate immune responses in the intestine. Nuclei in the epithelial cells and underlying intestinal tissue are stained with DAPI (cyan). Credit: Taylor Rice, Cincinnati Children’s How the microbiome influences tuft cells - This graphic describes a pathway in stem cells that allows development of tuft cells in the intestine. This process is dampened based on the levels of butyrate generated by the microbiome and suggests that targeting this pathway potentially offers new ways to protect against worm infection and manage the type of inflammatory reactions caused by food allergies. Credit: Emily Eshleman, Cincinnati Children’s. Experts at Cincinnati Children's have made a significant leap toward better understanding how these resident microbes instruct intestinal health in a far-reaching study published Jan. 30, 2024, in the journal Immunity. The research, led by immunologists and microbiome experts, Theresa Alenghat, VMD, PhD and Emily Eshleman, PhD, reveals a novel way to control allergic types of immune responses by adjusting how our intestines produce tuft cells, a lesser-understood element of our immune system. While many people know that our intestines are fundamental to absorbing nutrients from the food we eat, fewer people realize that the 22-foot tube curled into our abdomens also serves as the largest component of our immune defense against invading pathogens. Scientists have studied the intestine for many years, but even now they are learning surprising details about how it works. "This study shows that the microbiota—and products made by the microbiota—can dynamically control immune responses in the gut," Alenghat says. The research examines a reaction called type 2 immunity that occurs with chronic inflammatory conditions such as allergy and asthma. "We found that specific products made by bacteria in our gut can affect the power of type 2 reactions by controlling how many tuft cells form in the intestine's mucosal lining," Eshleman says. Until now, it was not clear if nor how the gut microbiome impacts tuft cells. But now that key elements involved in this developmental pathway have been identified, these findings open doors to designing new diet and microbiome approaches for preventing or promoting type 2 inflammation. A tale of fatty acids, organoids, stem cells— and worms Studying what goes on in the intestine has long been a scientific challenge because the gut environment is incredibly dynamic. In addition to all sorts of bacteria, fungi and viruses coming into the system, along with all the types of food and drink we consume, the intestine is constantly rebuilding itself. Our bodies continuously replace the entire epithelial lining from intestinal stem cells every two to five days. This means that the types of cells lining the intestine can often change, making them challenging to study in depth. In this project, Alenghat and colleagues used a combination of mouse models and human intestinal organoids (tiny spheres of functional human tissue grown in a lab dish) to measure tuft cell responses in action. Their goals were to figure out what drives the process during health and in the presence of inflammatory triggers. This is where worms enter the picture. Millions of people worldwide pick up "helminth infections", such as hookworms, roundworms and whipworms. It turns out that these parasites trigger similar type 2 immune reactions as a food allergy does. So by introducing worm infections to mice, researchers can study regulation of these immune responses in a controlled fashion without causing potentially dangerous allergic reactions in people. What's a tuft cell? Scientists figured out that cells exist back in the 1600s. But tuft cells weren't discovered until relatively recently—the 1950s. Their link to type 2 inflammation was made only within the last 10 years. These cells, so named because they are topped with fuzzy tufts of hair-like structures, emerge in widely variable, constantly changing numbers along the lining of the intestine. Researchers hunting for cures for parasite infections learned that the intestine forms large numbers of tuft cells during worm infections and that tuft cells sustain an immune cycle that gets rid of the worms. "This is one of many important reasons why we need a healthy intestinal immune system," Alenghat says. The Cincinnati Children's team shed light on how the tuft cell production process works. These special cells are created by stem cells that hide deep in pockets of the intestine called crypts. When the right trigger signal comes along, such as a worm infection, the production of tuft cells soars. However, the new study shows that bacteria that normally live in the intestine can play an inhibiting role that prevents stem cells from making tuft cells in both mouse and human intestine. Certain microbes chewing on dietary fiber emit butyrate, a common form of short-chain fatty acid that is often sold in health food stores as a potentially helpful dietary supplement. "Gut bacteria that emit lots of butyrate inhibit the activity of a protein called HDAC3, which stem cells need for making tuft cells," Eshleman says. "So, too much butyrate can mean not enough tuft cells—and that can be bad news when a helminth infection comes along." Next steps Much more research is needed before treatments aimed at controlling tuft cell numbers or function could be ready for patients, Alenghat says. One important future line of study will be seeking more understanding of how the life-long interplay of factors that change the microbiome also "train" the immune system, in good ways and bad. "The microbiome colonization process begins at birth, which suggests that there's a very early window that can set the course for microbiome-cell interactions for years to come," Alenghat says. Looking ahead, the paper suggests three possible ways to influence tuft cell production and potentially control the inflammation that occurs during chronic inflammatory conditions. Dietary regimens that can control fiber intake, up or down, can influence HDAC3 activity and change the number of tuft cells. Microbe-produced metabolites might be used to calibrate stem cell responses in the gut. Also, introducing new colonies of gut bacteria might be useful if people lack enough of the right types of bacteria. Successful treatment regimens down the road would likely require highly personalized approaches to re-calibrate, or re-balance the dynamics within the microbiome in healthy ways. "It's basically a constant balancing act," Alenghat says. "One of the struggles our bodies have is balancing the protective vs. pathologic aspects of our immune systems." About the study: In addition to Eshleman and Alenghat, Cincinnati Children's co-authors included: Taylor Rice, Crystal Potter, Amanda Waddell, PhD, Seika Hashimoto-Hill, DVM, PhD, Vivienne Woo, PhD, Sydney Field, Laura Engleman, and Fred Finkelman, MD, all with the Division of Immunobiology; Hee-Woong Lim, PhD, Division of Biomedical Informatics; and Lee Denson, MD, Division of Gastroenterology, Hepatology, and Nutrition. Funding sources for this research include several grants to investigators from the National Institutes of Health (DK114123, DK116868, DK095004, DK119694, K01DK131390, F32AI147591 and K01DK135647), the Kenneth Rainin Foundation, and the Burroughs Wellcome Fund. This project also is supported by the Center for Stem Cell & Organoid Medicine at Cincinnati Children's and NIH grants to the Digestive Health Center (P30 DK078392) and the Molecular Hematology Center of Excellence (U54 DK126108). SOURCE Cincinnati Children's Hospital Medical Center

First orphan drug designation for Nana-val granted in EBV+ solid tumors Seventh orphan drug designation for Nana-val globally; fifth granted by the FDA SAN DIEGO, Dec. 12, 2023 (GLOBE NEWSWIRE) -- Viracta Therapeutics, Inc. (Nasdaq: VIRX), a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide, today announced that the U.S. Food and Drug Administration (FDA) has granted an orphan drug designation (ODD) to Nana-val (nanatinostat in combination with valganciclovir), the company's all-oral investigational therapy targeting Epstein-Barr virus (EBV)-associated cancers, for the treatment of nasopharyngeal carcinoma (NPC). This represents the first ODD granted for Nana-val in Epstein-Barr virus-positive (EBV+) solid tumors and outside of EBV-associated lymphomas. The FDA previously granted Nana-val ODD for the treatment of T-cell lymphoma, post-transplant lymphoproliferative disorder, plasmablastic lymphoma, and EBV+ diffuse large B-cell lymphoma, not otherwise specified. "This orphan drug designation highlights the urgent need for new targeted treatment options for patients with rare diseases such as nasopharyngeal carcinoma, which is highly associated with EBV," said Mark Rothera, President and Chief Executive Officer of Viracta. "We are encouraged by the interim data from the Phase 1b/2 study of Nana-val in patients with recurrent or metastatic EBV-positive nasopharyngeal carcinoma, supporting the continued advancement of the study with a new split daily dosing regimen at higher doses. With sites open and enrolling the sixth dose cohort of the study, we are on track to expand into the Phase 2 portion in 2024. The growing clinical data in both the lymphoma and solid tumor settings, further validates the therapeutic potential of Nana-val to treat EBV-positive cancers, an underserved area of high unmet medical need.” The FDA’s Office of Orphan Products Development grants orphan status to drugs and biologics being developed to treat, diagnose, or prevent a rare disease or condition affecting fewer than 200,000 people in the U.S. ODD is designed to provide drug developers with various benefits to support the development of novel drugs, including the potential for seven years of market exclusivity upon FDA approval for the disease or condition for which the drug has ODD, eligibility for tax credits toward qualified clinical trial costs, exemptions from certain FDA application fees, reduced annual product user fees, clinical trial protocol design and drug development assistance, and potential qualification for expedited drug development programs. About the Phase 1b/2 Study of Nana-val in R/M EBV+ NPC and Other EBV+ Solid Tumors This Phase 1b/2 trial (NCT05166577) is an open-label, multinational clinical trial evaluating Nana-val alone and in combination with pembrolizumab. The Phase 1b dose escalation part is designed to evaluate safety and to select the recommended Phase 2 dose (RP2D) of Nana-val in patients with recurrent or metastatic (R/M) Epstein-Barr virus-positive (EBV+) nasopharyngeal carcinoma (NPC). Along with the U.S. Food and Drug Administration’s Project Optimus initiative, at the start of Phase 2, up to 40 patients with R/M EBV+ NPC will be randomized to receive either the RP2D or a dose level below the RP2D in a dose-optimization cohort. Once the RP2D has been confirmed, up to 60 patients with R/M EBV+ NPC will be randomized to receive Nana-val at the RP2D with or without pembrolizumab to further evaluate antitumor activity, safety and tolerability, pharmacokinetics, and potential pharmacodynamic biomarkers. Additionally, patients with other advanced EBV+ solid tumors will be enrolled to receive Nana-val at the RP2D in a Phase 1b dose expansion cohort. About Nana-val (Nanatinostat and Valganciclovir) Nanatinostat is an orally available histone deacetylase (HDAC) inhibitor being developed by Viracta. Nanatinostat is selective for specific isoforms of Class I HDACs, which are key to inducing viral genes that are epigenetically silenced in Epstein-Barr virus (EBV)-associated malignancies. Nanatinostat is currently being investigated in combination with the antiviral agent valganciclovir as an all-oral combination therapy, Nana-val, in various subtypes of EBV-associated malignancies. Ongoing trials include a pivotal, global, multicenter, open-label Phase 2 basket trial in multiple subtypes of relapsed or refractory (R/R) EBV+ lymphoma (NAVAL-1) as well as a multinational Phase 1b/2 clinical trial in patients with recurrent or metastatic (R/M) EBV+ NPC and other EBV+ solid tumors. About EBV-Associated Cancers Approximately 90% of the world’s adult population is infected with EBV. Infections are commonly asymptomatic or associated with mononucleosis. Following infection, the virus remains latent in a small subset of cells for the duration of the patient’s life. Cells containing latent virus are increasingly susceptible to malignant transformation. Patients who are immunocompromised are at an increased risk of developing EBV-positive (EBV+) lymphomas. EBV is estimated to be associated with approximately 2% of the global cancer burden including lymphoma, nasopharyngeal carcinoma (NPC), and gastric cancer. About Viracta Therapeutics, Inc. Viracta is a clinical-stage precision oncology company focused on the treatment and prevention of virus-associated cancers that impact patients worldwide. Viracta’s lead product candidate is an all-oral combination therapy of its proprietary investigational drug, nanatinostat, and the antiviral agent valganciclovir (collectively referred to as Nana-val). Nana-val is currently being evaluated in multiple ongoing clinical trials, including a pivotal, global, multicenter, open-label Phase 2 basket trial for the treatment of multiple subtypes of relapsed or refractory (R/R) Epstein-Barr virus-positive (EBV+) lymphoma (NAVAL-1), as well as a multinational, open-label Phase 1b/2 clinical trial for the treatment of patients with recurrent or metastatic (R/M) EBV+ nasopharyngeal carcinoma (NPC) and other advanced EBV+ solid tumors. Viracta is also pursuing the application of its “Kick and Kill” approach in other virus-related cancers. For additional information, please visit Forward-Looking Statements This communication contains "forward-looking" statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, without limitation, statements regarding: the details, timeline and expected progress for Viracta's ongoing and anticipated clinical trials and updates regarding the same, the Company’s expectations of the significance and implications of the preliminary interim data from its clinical trials and preclinical studies disclosed herein, the Company’s expectations related to the FDA submission process and timelines and expectations regarding our target patient populations. Risks and uncertainties related to Viracta that may cause actual results to differ materially from those expressed or implied in any forward-looking statement include, but are not limited to: Viracta's ability to successfully enroll patients in and complete its ongoing and planned clinical trials; Viracta's plans to develop and commercialize its product candidates, including all oral combinations of nanatinostat and valganciclovir; the timing of initiation of Viracta's planned clinical trials; the timing of the availability of data from Viracta's clinical trials; previous preclinical and clinical results may not be predictive of future clinical results; the timing of any planned investigational new drug application or new drug application; Viracta's plans to research, develop, and commercialize its current and future product candidates; the clinical utility, potential benefits, and market acceptance of Viracta's product candidates and Viracta's ability to manufacture or supply nanatinostat, valganciclovir, and pembrolizumab for clinical testing. If any of these risks materialize or underlying assumptions prove incorrect, actual results could differ materially from the results implied by these forward-looking statements. Additional risks and uncertainties that could cause actual outcomes and results to differ materially from those contemplated by the forward-looking statements are included under the caption "Risk Factors" and elsewhere in Viracta's reports and other documents that Viracta has or will file, with the SEC from time to time and available at The forward-looking statements included in this communication are made only as of the date hereof. Viracta assumes no obligation and does not intend to update these forward-looking statements, except as required by law or applicable regulation. Investor Relations Contact: Ashleigh Barreto Head of Investor Relations & Corporate Communications Viracta Therapeutics, Inc. abarreto@viracta.com SOURCE Viracta Therapeutics, Inc.