Persian Gulf Syndrome

March 08, 2024 -- Biosplice Therapeutics, Inc. (“Biosplice”) announced today that its collaboration with The Roskamp Institute (“Roskamp”), aimed at developing novel therapies for TBI using Biosplice’s promising small molecule DYRK (dual-specificity tyrosine phosphorylation-regulated kinase) inhibitors has been selected for funding by the DoD office of the Congressionally Directed Medical Research Programs (CDMRP). As part of the collaboration, the DoD TBIPHRP Award will fund Roskamp to undertake preclinical development in their well characterized TBI models using Biosplice’s DYRK inhibitors. This translational work could lead to future clinical trials for TBI patients. The data from this collaboration are anticipated to inform the development of Biosplice’s DYRK inhibitor class in the treatment of degenerative neurological conditions, including various tauopathies. TBI, along with Alzheimer’s Disease, certain Frontotemporal Dementias and Amyotrophic Lateral Sclerosis (ALS) are in a class of neurological disorders characterized by an aggregation of harmful tau proteins. Because the DYRK protein plays a key role in the formation of harmful tau protein aggregates, Biosplice believes that its potent and selective DYRK inhibitors can potentially constitute effective, first-in-class therapies. “We are pleased to collaborate with Roskamp in this exciting research program endeavoring to address a great unmet need for effective therapies for TBI,” said Dr. Yusuf Yazici, Chief Medical Officer of Biosplice. “DoD’s selection of the Biosplice/Roskamp collaboration validates years of our industry-leading development of highly-selective DYRK inhibitors.” Erich Horsley, CFO and CBO of Biosplice, added, “Over the past 10 years, our team at Biosplice has considerably deepened its chemical and clinical expertise in selective inhibition of DYRK and CLK kinases. This collaboration with Roskamp will help accelerate the development of our novel neurology therapies, ranging from TBI to ALS to Alzheimer’s disease.” This award builds upon more than four years of scientific collaboration between Roskamp and Biosplice. Previous research conducted by Roskamp has demonstrated efficacy in TBI animal models with Biosplice’s first-generation DYRK inhibitors. Since opening its doors in 2003, The Roskamp Institute, a 501(c)(3) nonprofit organization, has been a leader in the global effort to better understand and treat diseases of the mind. The foundation for the Institute’s work was set more than a decade ago by the Institute’s two lead researchers, Drs. Michael Mullan and Fiona Crawford, who were key members of a pioneering team of scientists who, in the early 1990s, discovered the first known mutations causing early onset Alzheimer’s Disease in the amyloid gene. Research at Roskamp is focused on Alzheimer’s Disease, Traumatic Brain Injury, Post-Traumatic Stress Disorder, Gulf War Illness and Red Tide. Biosplice stands at the forefront of research concentrating on the study and regulation of Cdc2-like kinases (CLKs) and dual-specificity tyrosine-regulated kinases (DYRKs). These kinases play pivotal roles in cell cycle regulation, splicing, and neurodevelopment, marking them as critical targets for therapeutic intervention in a range of diseases, including osteoarthritis, cancer, neurological disorders, and diabetes. With a robust chemical platform for kinase inhibition and a deep understanding of kinase signaling pathways, Biosplice leverages cutting-edge technologies to discover and develop highly selective kinase inhibitors. Biosplice’s drugs in clinical development include lorecivivint for osteoarthritis (in Phase 3) and cirtuvivint for numerous cancers, with a broad pre-clinical pipeline that encompasses Alzheimer’s disease, diabetes and other degenerative conditions. The content above comes from the network. if any infringement, please contact us to modify.

Gulf War Illness (GWI), which affects approximately 250,000 U.S. veterans, has been found to significantly reduce the ability of white blood cells to make energy and creates a measurable biochemical difference in veterans who have the disease. The finding comes from a physician who noticed GWI symptoms paralleled those of mitochondrial diseases. Analysis revealed significantly lower levels of extracellular acidification and oxygen consumption in the white blood cells of veterans with GWI. A new Duke University-led study finds that Gulf War Illness (GWI), which affects approximately 250,000 U.S. veterans, significantly reduces their white blood cells' ability to make energy and creates a measurable biochemical difference in veterans who have the disease. "Historically, GWI has been diagnosed based on a veteran's self-reported symptoms, such as exercise-induced fatigue, indigestion, dizziness, insomnia, or memory problems. There's been no objective biochemical or molecular measurements doctors could use to diagnose it," said Joel Meyer, professor of environmental genomics at Duke's Nicholas School of the Environment, who led the new study. The new study provides measurements accessible in blood samples, which, though not sufficient to serve as a stand-alone diagnostic test, could be useful to help improve treatment for veterans suffering from Gulf War Illness by giving doctors a new way to assess whether a prescribed treatment is helping, Meyer said. "Knowing this is an energetic deficiency can help us zero in on more effective ways to relieve the symptoms," Meyer said. "Blood tests, repeated over the course of the treatment, would show if a veteran's white blood cells are responding to a treatment and producing more energy." He and his coauthors from Duke, the U.S. Department of Veteran Affairs' War-Related Illness and Injury Study Center, and the New Jersey Medical School published the new peer-reviewed paper Nov. 1 in the open-access journal PLOS ONE. Their research reveals that Gulf War Illness inhibits white blood cells' energy production by impairing the workings of the cells' mitochondria, structures within the cell which extract energy from food and convert it into the chemical power needed to fuel growth, movement and other bodily processes and functions. Mitochondria are often referred to as the 'power plants' of the cell. "The idea to investigate the role mitochondria might be playing in GWI came from Mike Falvo, one of my coauthors from Veteran Affairs and the New Jersey Medical School, who had noticed that a lot of GWI symptoms were similar to those associated with mitochondrial diseases," said Meyer. "So, we analyzed mitochondrial respiration and extracellular acidification, which are proxies for energy generation, in the white blood cells of 114 Gulf War veterans, 80 of whom had been diagnosed with GWI. We also looked for evidence of mitochondrial DNA damage and nuclear DNA damage." The analyses revealed no evidence of DNA damage, but they did show significantly lower levels of extracellular acidification and oxygen consumption in the white blood cells from veterans with GWI -- signs that their mitochondria were generating less energy. Follow-up blood tests on about a third of the veterans showed that some of these levels could vary over time, but the general pattern remained: the cells of veterans with GWI produced less energy. The cause of Gulf War Illness is still unknown. To determine if environmental factors might play a role, Meyer and his colleagues turned to the veterans' surveys of self-reported symptoms and their written recollections of their deployments. "We found veterans who recalled being exposed to pesticides and pyridostigmine bromide, a drug used during the Gulf War as a pretreatment to protect troops from the harmful effects of nerve agents, were more likely to get GWI after deployment," Meyer said. "An interesting question is how these effects have persisted so long after the exposures." Coauthors on the new paper were William Pan and Ian Ryde of Duke; Thomas Alexander, Jacquelyn Klein-Adams and Duncan Ndirangu of the U.S. Department of Veteran Affairs' War-Related Illness and Injury Study Center (WRIISC); and Michael Falvo of WRIISC and the New Jersey Medical School at Rutgers Biomedical and Health Science.

Scientists contest longstanding hypothesis about mysterious illness affecting Gulf War veterans, providing first direct evidence that symptoms are driven by impaired mitochondria. Gulf War Illness (GWI) is a chronic multisymptom health condition affecting one-third of all veterans who served in the 1991 Gulf War, most of whom remain afflicted more than 30 years later. Common symptoms include fatigue, headaches, muscle aches, joint pain, diarrhea, insomnia and cognitive impairment. The condition is believed to have been triggered by veterans' exposure to environmental toxins. However, its exact mechanism in the body continues to be debated, making it difficult to diagnose and treat. The prevailing notion is that inflammation is the driving force of the symptoms, as inflammatory markers are modestly higher in affected veterans than in healthy controls. However, a rival hypothesis suggests mitochondria -- the energy-producing organelle found in most cells -- may be the true source of the symptoms. In a new study, researchers at University of California San Diego School of Medicine put both ideas head-to-head, directly assessing mitochondrial impairment and inflammation in 36 individuals, 19 of whom were veterans with GWI. The findings, published July 12, 2023 in Scientific Reports, suggest that impaired mitochondrial function, and not inflammation, is the main driver of GWI symptoms and should be the primary target of future clinical interventions. "This is a radical rethinking of the pathology of GWI," said corresponding author Beatrice Golomb, MD, PhD, professor of medicine at UC San Diego School of Medicine. "For veterans who have long struggled to get effective care, this discovery could be a real game changer." To evaluate the respective roles of mitochondrial function and inflammation in GWI, the researchers acquired muscle biopsies from the study participants and measured the levels of mitochondrial respiratory chain function (MRCF). Inflammation was assessed through participants' blood levels of high-sensitivity C-reactive protein (hsCRP), a common marker of peripheral inflammation. The researchers then compared this data to the participants' GWI symptoms and found that the severity of symptoms could be predicted by their degree of mitochondrial impairment, but not by their degree of inflammation. Further statistical analyses found that 17 of the 20 most common GWI symptoms were statistically related to mitochondrial function. In contrast, only one of the 20 symptoms met this criterion for inflammation. Another set of analyses revealed that the degree to which participants' mitochondria were compromised in converting fat to energy was strongly related to the degree of inflammation in GWI patients, but not in controls. Reduced activity of this process, called fatty acid oxidation, is known to trigger cell death, which then leads to inflammation. Thus the researchers say this suggests that mitochondrial dysfunction may be the reason inflammation is higher in GWI patients. "Inflammation does appear to be linked to GWI, but our work suggests that it's actually a side effect of the primary issue, which is impaired cell energy," said Golomb. The researchers also note that many GWI symptoms are expected outcomes of mitochondrial dysfunction. For example, muscles rely heavily on fat to fuel them, so if mitochondrial dysfunction leads to impaired fatty acid oxidation in GWI patients, this could explain the muscle aches and physical fatigue they often experience. Indeed, muscle symptoms in GWI correlated most strongly with the degree of impairment in mitochondrial fatty acid oxidation. Conversely, the brain relies mostly on sugar for energy, and brain symptoms in GWI related most strongly to impairment in mitochondrial energy production using sugar as a fuel. The findings also have possible implications for other health conditions, including different forms of toxin exposure, aging and even heart disease. Many of these conditions are marked by increased inflammation, yet often do not respond well to anti-inflammatory drugs. Golomb and colleagues argue that mitochondrial impairment may be an underlying cause for these conditions, creating opportunities for new therapeutic strategies. "This is the first time that direct evidence for the mitochondrial hypothesis of GWI has been reported," said Golomb. "We hope that it will lead to improved treatment plans for the veterans who have long struggled with this mysterious illness." Co-authors of the study include: Roel Sanchez Baez, Jan M. Schilling, Mehul Dhanani, McKenzie J. Fannon, Brinton K. Berg, Bruce J. Miller, Pam R. Taub and Hemal H. Patel, all at UC San Diego.