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

ROCKVILLE, Md., Sept. 11, 2023 /PRNewswire/ -- Shuttle Pharmaceuticals Holdings, Inc. (Nasdaq: SHPH), a discovery and development stage specialty pharmaceutical company focused on improving the outcomes of cancer patients treated with radiation therapy (RT), today announced the expansion of its patent portfolio following the issuance of a Canadian patent for its Histone Deacetylase (HDAC) inhibitor platform technology titled "Dual Function Molecules for Histone Deacetylase Inhibition and Ataxia Telangiectasia Mutated (ATM) Activation and Methods of Use Thereof." HDAC inhibitors have been described as "a novel class of drugs that target enzymes involved in regulation of critical cellular functions that can inhibit cancer growth and activate cellular immunity," according to Scott Grindrod, PhD, lead inventor and Laboratory Director at Shuttle Pharmaceuticals. The Company's HDAC pre-clinical inhibitor platform includes: SP-2-225 is Shuttle Pharma's pre-clinical Class IIb selective HDAC inhibitor that affects histone deacetylase HDAC6. SP-2-225 has effects on the regulation of the immune system. The interactions of radiation therapy with the immune response to cancers are of great current interest, offering insight into potential mechanisms for primary site and metastatic cancer treatment. For this reason, Shuttle Pharma selected SP-2-225 as the candidate lead HDAC inhibitor for preclinical development. Shuttle Pharma is advancing drug manufacture and IND-enabling studies with the goal of enabling a Phase I clinical trial in 2024. With the introduction of check-point inhibitors, CAR-T therapies and personalized medicine in cancer, regulation of the immune response following RT continues to be of significant clinical and commercial interest. SP-1-161 is Shuttle Pharma's pre-clinical candidate lead HDAC inhibitor, radiation sensitizing candidate product. This pan HDAC inhibitor initiates the mutated ataxia-telangiectasia response pathway. Using rational drug design, Shuttle Pharma discovered HDAC inhibitors and ATM activators capable of radiation sensitizing cancer cells and protecting normal cells. The candidate drug may serve as a direct chemotherapeutic agent or as a radiation sensitizer for treating cancers. In preclinical studies, SP-1-161 protected normal breast epithelial cells (184A1) following exposure to ionizing radiation while increasing sensitivity of breast cancer cells (MCF7). SP-1-161 provides this dual function in a single molecule and this molecule is differentiated from other HDAC inhibitors by treatment of cancers while protecting normal cells. SP-1-303 is Shuttle Pharma's pre-clinical selective Class I HDAC inhibitor that preferentially affects histone deacetylases HDAC1 and HDAC3 and is a member of the Class I HDAC family. SP-1-303 data show direct cellular toxicity in estrogen receptor (ER) positive breast cancer cells. "We continue to expand our patent portfolio surrounding our HDAC inhibitor platform," stated Anatoly Dritschilo, M.D., CEO of Shuttle Pharmaceuticals. "We look forward to advancing our developments by providing dual function compounds that may inhibit HDAC and activate ATM to treat certain cancers, such as breast, multiple myeloma and lung, as well as neurological disorders, and immunological disorders. Our objective is to improve patient outcomes by increasing sensitivity to radiation while protecting normal tissues." About Shuttle Pharmaceuticals Founded in 2012 by faculty members of the Georgetown University Medical Center, Shuttle Pharmaceuticals is a discovery and development stage specialty pharmaceutical company focused on improving the outcomes for cancer patients treated with radiation therapy (RT). Our mission is to improve the lives of cancer patients by developing therapies that are designed to maximize the effectiveness of RT while limiting the side effects of radiation in cancer treatment. Although RT is a proven modality for treating cancers, by developing radiation sensitizers, we aim to increase cancer cure rates, prolong patient survival and improve quality of life when used as a primary treatment or in combination with surgery, chemotherapy and immunotherapy. For more information, please visit our website at . Safe Harbor Statement Statements in this press release about future expectations, plans and prospects, as well as any other statements regarding matters that are not historical facts, may constitute "forward-looking statements." These statements include, but are not limited to, statements concerning the development of our company. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," "target," "will," "would" and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including factors discussed in the "Risk Factors" section of Shuttle Pharma's Annual Report on Form 10-K for the year ended December 31, 2022, filed with the SEC on March 15, 2023, its Quarterly Reports on Form 10-Q for the periods ended March 31, 2023 and June 30, 2023, filed with the SEC on May 25, 2023 and August 14, 2023, respectively, as well other SEC filings. Any forward-looking statements contained in this press release speak only as of the date hereof and, except as required by federal securities laws, Shuttle Pharmaceuticals specifically disclaims any obligation to update any forward-looking statement, whether as a result of new information, future events or otherwise. Shuttle Pharmaceuticals Anatoly Dritschilo, M.D., CEO 240-403-4212 [email protected] Investor Contacts Lytham Partners, LLC Robert Blum 602-889-9700 [email protected] SOURCE Shuttle Pharmaceuticals Holdings, Inc.