SP140

There's a potential new therapeutic target for Crohn's disease, a large study says risk of myocarditis is much higher after COVID-19 than vaccination and a mouse study sparks hope for a potential cure for childhood brain tumors. Here's a look at just some of this week's most intriguing research news. Potential New Therapeutic Target for Crohn's Disease Researchers with Massachusetts General Hospital unraveled new mechanisms behind Crohn's disease. Chromatin is a combination of DNA and proteins that form chromosomes, and this structure can affect gene expression. Certain chromatin "readers" play a part in monitoring chromatin's response to the environment. The research team found that mutations within one reader, Speckled Protein 140 (SP140), were linked with an increased risk of certain immune diseases, including Crohn's disease. They published their research in the journal Cell. Kate L. Jeffrey, Ph.D., principal investigator of immunology at MGH and an associate professor of medicine at Harvard Medical School, said, "The work broadens our understanding of epigenetics in health - or the physical changes in cells' DNA structure that affect the expression of genes in response to environmental cues. Importantly though, it revealed how dysregulation of epigenetic factors drive diseases such as Crohn's that are rising in incidence because of the complex interplay of genes plus environment." Expression of SP140 is uniquely restricted to immune cells, including macrophages. These immune cells engulf and kill microorganisms, remove dead cells and stimulate other immune cells into action. They found that SP140 represses topoisomerases (TOP), enzymes that assist DNA in untangling during replication. Loss of SP140 in mice and humans allows uncontrolled TOP activity, which leads to abnormal gene expression and the killing of bacteria by macrophages that lead to intestinal abnormalities. Inhibiting TOP halted these defects in a mouse model. Myocarditis Risk Much Higher After COVID-19 Infection Versus After Vaccine In rare situations, cases of heart inflammation, or myocarditis, were observed in people after receiving a COVID-19 vaccine. A new study of almost 43 million people 13 years and older who received at least a single dose of a COVID-19 vaccine in England found that the risk of myocarditis in unvaccinated people after COVID-19 infection was 11 times higher. This is compared to people who developed myocarditis after receiving a vaccine or booster. The data looked at people who received the shots between Dec. 1, 2020, and Dec. 15, 2021. Investigators conducted the research at the University of Oxford. The vaccines involved were Pfizer-BioNTech, Moderna and the AstraZeneca-University of Oxford shots. How Enhancer Mutations Cause Disease Researchers from the Center for Genomic Regulation have identified mutations in specific gene sequences known as enhancers that are associated with pancreatic malformations. The sequence is dubbed EnhP, and mutations in this particular DNA sequence lead to pancreas malformations. In mice, these mutations caused underdeveloped pancreas and insulin-deficient diabetes. They don't appear to disrupt the DNA sequence of a gene. Enhancers appear hundreds of thousands of times within the genome and act as switches to turn on transcription of their target genes in the correct tissues. The researchers believe these enhancer mutations may explain diseases where laboratory assays have yet to identify gene mutations that cause these diseases. The only role of EnhP is to activate a cluster of enhancers that regulate PTF1A, the pancreas-associated transcription factor 1a, in the first cells that form the pancreas during fetal development. Potential Cure for Childhood Brain Tumors Investigators at the Karolinska Institute, Massachusetts General Hospital and the Harvard Stem Cell Institute have identified what they call a potentially curative treatment of neuroblastoma in mice when combined with chemotherapy. The research group demonstrated that DHODH blockers appear to cure neuroblastoma in mice if given with chemotherapy. In other studies, DHODH blockers have been shown to be well tolerated in humans for other diseases. In analyzing patient data from more than 600 children with neuroblastoma, they found that tumors with high levels of DHODH were more aggressive and deadly. They utilized a DHODH blocker named Brequinar. The drug decreased the activity of the MYCN gene, which drives tumor growth. But after treatment, the tumors started growing again. They then combined Brequinar with chemotherapy, which cured the mice with neuroblastoma. Treatment Eradicated Mesothelioma Tumors Within Days Working in mice, researchers with Rice University and Baylor College of Medicine used a cytokine "drug factory" implant and a checkpoint inhibitor to eliminate advanced-stage mesothelioma tumors. The implants are tiny beads, no larger than the head of a pin, that produce drugs. The research team implanted them next to tumors, where the beads then produced continuous, high doses of interleukin-2 (IL-2), a compound that activates white blood cells. The alginate beads carry tens of thousands of genetically engineered cells designed to manufacture IL2 and appeared to eradicate the tumors in less than a week. They used the beads in conjunction with an anti-PD-1 checkpoint inhibitor. The researchers have had discussions with the U.S. FDA and expect to begin running a clinical trial using the beads late next year. "The preclinical data reported in our latest manuscript helped justify initiating a second clinical trial for patients suffering from mesothelioma and other lung cancers with pleural metastasis," Omid Veiseh, Ph.D., a bioengineer at Rice who invented the beads, said. "We have held meetings with the FDA and expect to initiate a second trial for this patient population in the latter half of 2023."

Researchers have found that inhibitors of an enzyme called Speckled Protein 140 can reverse intestinal abnormalities in mice with inflammation characteristic of Chron's disease. BOSTON – The structure of chromatin—the mixture of DNA and proteins that form chromosomes—can affect gene expression, and certain chromatin “readers” are important for monitoring this structure often in response to environmental cues. BOSTON – The structure of chromatin—the mixture of DNA and proteins that form chromosomes—can affect gene expression, and certain chromatin “readers” are important for monitoring this structure often in response to environmental cues. Mutations within one such reader, called Speckled Protein 140 (SP140), are associated with an increased risk of certain immune diseases, including Crohn’s disease, a type of inflammatory bowel disease. New research led by investigators at Massachusetts General Hospital (MGH) and published in Cell provides insights into the mechanisms behind this link, pointing to potential therapeutic targets. SP140 expression is uniquely restricted to immune cells such as macrophages, which surround and kill microorganisms, remove dead cells, and stimulate the action of other immune cells. Protein analyses by Kate L. Jeffrey, PhD, a principal investigator of immunology at MGH and an associate professor of medicine at Harvard Medical School, and her colleagues revealed that SP140 represses topoisomerases (TOP), which are enzymes that help DNA untangle during replication. The team also found that in humans and mice, SP140 loss resulted in unleashed TOP activity, ultimately leading to defective gene expression and bacterial killing by macrophages that caused intestinal abnormalities. Inhibiting TOP rescued these defects in mice with inflammation characteristic of Crohn’s disease, a condition that remains incurable by surgical or therapeutic interventions. “Applying a combination of human genetics, proteomics, biochemistry, utilization of primary immune cells from Crohn’s disease individuals, and in vivo animal studies, our study highlights the power of examining human disease associated genetic mutations to advance mechanistic understanding of disease,” says Jeffrey. “The work broadens our understanding of epigenetics in health—or the physical changes in cells’ DNA structure that affect the expression of genes in response to environmental cues. Importantly though, it revealed how dysregulation of epigenetic factors drive diseases such as Crohn’s that are rising in incidence because of the complex interplay of genes plus environment.” Several TOP inhibitors are approved for the treatment of certain cancers, and many in the drug class are being tested in ongoing cancer clinical trials. These latest findings indicate that clinical trials should also test their effectiveness against Crohn’s disease. Additional co-authors include Hajera Amatullah, Isabella Fraschilla, Sreehaas Digumarthi, Julie Huang, Fatemeh Adiliaghdam, Gracia Bonilla, Lai Ping Wong, Marie-Eve Rivard, Claudine Beauchamp, Virginie Mercier, Philippe Goyette, Ruslan I. Sadreyev, Robert M. Anthony, and John Rioux. This study was supported by the Canadian Institutes of Health Research, the Canada Foundation for Innovation, the National Institutes of Health and the MGH Research Scholar Program. Dr. Jeffrey is a John Lawrence MGH Research Scholar 2020-2025. Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The Mass General Research Institute conducts the largest hospital-based research program in the nation, with annual research operations of more than $1 billion and comprises more than 9,500 researchers working across more than 30 institutes, centers and departments. In July 2022, Mass General was named #8 in the U.S. News & World Report list of "America’s Best Hospitals." MGH is a founding member of the Mass General Brigham healthcare system.