FALL NEWSLETTER 2025     Dear Friends, Propel a Cure is thrilled to continue to bring you regular updates from labs, which, because of your support, are utilizing groundbreaking approaches in their quest to find the underlying causes and mechanisms behind Crohn's disease. We are grateful to these incredible researchers for dedicating their talents to inflammatory bowel disease (IBD) research and for drafting quarterly summaries that we can share with you publicly, providing transparency. Scientists engaged in novel research don't have it easy; it requires a constant scramble for funds, dedication beyond belief, and the courage to seek new avenues outside what's been tried before. With your help, they are making progress that will one day bring us cures for Crohn's disease. HOPE BUILDERS WEEK September 15-21 Propel a Cure's Hope Builders Week is September 15-21. Hope Builders are recurring donors who play a huge part in making Crohn's disease cures possible! By joining our movement and committing to just $10 or more a month to innovative IBD research, you're giving power to patients and becoming part of the solution. As one of our Hope Builders, you'll receive invitations to special virtual events, recognition in our quarterly e-newsletter, and our promise to bring you quarterly updates about the crucial, cure-focused studies you are helping to fund. Here is how becoming a Hope Builder adds up to BIG IMPACT: $25 monthly ($300 annually): covers 1 month of processing and handling of biomedical tissue samples $50 monthly ($600 annually): covers 2 months supply of chemicals & reagents $100 monthly ($1200 annually): covers 1 month of acquisition, housing, & data analysis of laboratory mouse models $200 monthly ($2400 annually): covers 2 months of stipend for a post-doctoral research assistant affiliated with a Propel a Cure-sponsored study To become a Hope Builder, please visit propelacure.org/donate and choose the monthly giving option. Thank you! HOPE BUILDER RECURRING DONORS Raihaneh Bokharai Sue Cragg Vince Cvijanovic Natalie Muccioli Emery Dina Fiatarone Stephen Hall Gustovao Nonohay Kathleen Pinckney Anthea Pritchard Devin Rasmussen Lakshmi Sampath Eric Voisard RESEARCH UPDATE This special message is from Dr. Pradipta Ghosh, whose lab is receiving funding for this project from your donations: Our researchers have mapped a druggable pathway that could lead to therapies for Crohn's patients who have run out of options. Work is now underway to translate this discovery into medicines that can truly change lives. However, science can only go as far as resources allow. That's where you come in. With your support, we can fuel this research, speed new treatments, and bring light to families living in the shadow of IBD. Together, we can help flip the switch – from suffering to healing. Please help us fully fund this project by giving at propelacure.org/donate. Dr. Pradipta Ghosh Photo by Kyle Dykes, UC San Diego GHOSH LAB, UC SAN DIEGO SEPTEMBER 2025 UPDATE SCIENTISTS IDENTIFY "TOGGLE SWITCH" TO TURN ON GUT HEALING Using advanced computer models powered by machine learning, Ghosh Lab researchers have discovered that, in many patients, harmful bacteria pile up in the gut. Normally, our body's immune "clean-up crew" cells, called macrophages, remove these threats. But in IBD, the very macrophages meant to both fight infection and calm inflammation seem to fail. More specifically, the team has uncovered with mathematical precision a hidden "battlefield" inside these cells. Bacteria have learned to hijack a universal cell signal called cAMP—a kind of rapid-fire text messaging system in our bodies. When cAMP runs wild, macrophages lose their ability to destroy germs, leaving patients trapped in cycles of infection and inflammation. The team has also found our bodies carry a natural toggle switch that can reset the system. A sensor called NOD2 and a partner molecule called GIV work like a tag-team, handing off control to stop cAMP overload and restore balance. When this switch is "on," macrophages clear bacteria, protect the gut lining, and bring healing. Even more exciting, Ghosh Lab researchers have already shown, by recreating the battlefield using end-to-end human organoids and immune cells in culture dishes with microbes, that restoring this switch with specially designed molecules can rescue sick cells in the lab.   WOOLSTON LAB, NORTHEASTERN UNIVERSITY SEPTEMBER 2025 UPDATE ENGINEERED BACTERIA DEGRADES INFLAMMATION-ASSOCIATED MOLECULE Earlier this year, Propel a Cure, in partnership with the Mendez Family Foundation, contributed $100,000 to a project at the Woolston Lab at Northeastern University to determine the role of the molecule hydrogen sulfide (H2S) – produced primarily by gut microbes – in intestinal inflammation in IBD. Over the last few months, the lab has made progress in understanding the fundamental role of H2S in Crohn's disease. They have now generated proof-of-concept data that their engineered bacteria can degrade H2S in the mouse gut. This is a critical step toward developing a probiotic to degrade intestinal H2S, which they believe plays a key role in exacerbating Crohn's inflammation.   PROMAKHOS THERAPEUTICS SEPTEMBER 2025 UPDATE NEW THERAPY EXHIBITS PROMISING RESULTS IN MICE Note: Promakhos Therapeutics has successfully concluded the Propel a Cure-funded portion of the following study. Your donations have been crucial to generating the data this team needs to pursue additional funding from other sources in their efforts to transition from the lab to the clinic with this promising, cure-focused research. Boston-area Promakhos Therapeutics, which received a $100,000 grant from Propel a Cure donors, is investigating what they believe to be a deficiency in the mucosal innate immune response in Crohn's patients and an oral, nonimmunosuppressive therapy to correct it. They are now in the process of testing a promising therapeutic compound in mice. Over the summer, the team finalized the analysis of their study involving the transplantation of stool from patients with active Crohn's disease into mice to establish a humanized mouse model of colon inflammation. As a reminder, colon inflammation in this model worsens for 3-4 days and then heals over the next 10-15 days. Starting at the peak of inflammation (day 4), the researchers administered their compound once per day through the mouth to restore the natural activity of the bacterial molecules in the mouse gut. The researchers previously observed that treatment with their compound led to a reduction in disease symptoms by 73% on day 8 and by 92% on day 10, while placebo-treated mice showed a 43% and 67% reduction by day 8 and day 10. The researchers have now also observed that their compound significantly reduced histologically determined inflammation and disease in the colon by 25% on day 10, as compared to placebo-treated mice. This is a comparable analysis to observing endoscopic healing. Combined, these results validate that their compound significantly accelerated healing of acute colon inflammation in these Crohn's humanized mice. Besides this acute model, the researchers have also evaluated the therapeutic effect of their compound in a chronic mouse model of colon inflammation. In this model, naïve CD4+ T cells (a component of our adaptive immune system) are injected into mice. These T cells are then activated by the gut microbiome and initiate a progressively worsening inflammation in the colon that becomes severe over 40 days. The researchers administered their compound or placebo once every day starting on day 5 by mouth and then tracked symptom and colon inflammation development until day 40. Treatment with their compound significantly reduced symptoms by 27% (total disease activity index), the amount of inflammatory T cells in the colon by 52% (cytometry) and, most importantly, colon inflammation by 48% (histological analysis). This apparent difference between the reduction in overall clinical symptoms and colon inflammation might be expected since in this model the injection of T cells not only causes inflammation in the gut, but also across the body, while the researchers' compound is designed to ameliorate bowel inflammation. Finally, the researchers also evaluated twice daily oral treatment with a JAK inhibitor, which works like the drug Rinvoq. In comparison with the Promakhos-developed therapeutic, this inhibitor reduced symptoms by 2%, T cells in the bowel by 5%, and colon inflammation by 21%. BEHIND THE SCENES OF PROPEL A CURE Over the summer, Propel a Cure President & CEO Angela Clark participated in two interviews – a podcast and a written blog – where she shared the origins of Propel a Cure as well as its approach to advancing Crohn's research to lay the groundwork for cures. To watch the video discussion, which is from the popular About IBD podcast hosted by Amber Tresca, click here. To read the blog interview with our organizational partner IBD Connect, click here. WELLNESS COMPANION NEW IOS APP SEEKING IBD PATIENT TESTERS The creators of Fathom, a new AI-powered wellness companion app designed by a Crohn's patient, are inviting IBD patients to test its new app. Fathom is designed to track diagnosis history, medications, symptom patterns, food and water intake, mood, sleep, and other variables to uncover patterns and insights. To sign up as a beta tester, join the waitlist on the Fathom Care website. POWER OF DAF GIVING CHARITABLE DONOR ADVISED FUNDS Do you have a donor-advised fund (DAF)? A DAF is a charitable savings account (like a 401k for giving) and is a powerful way to help transform Crohn's research, works for every budget, and offers tax savings. Propel a Cure is deeply grateful for check or electronic DAF contributions, with over 98% earmarked specifically for the labs we sponsor. We also participate in DAFpay, allowing you to give online directly from your DAF via our donation page. If you would like to find out more about DAFs or about how to set one up, click here. STEM CELL TRIAL OPENS HOPE BIOSCIENCES RESEARCH FOUNDATION Texas-based Hope Biosciences Research Foundation has announced that it is now enrolling for a Phase II, FDA-authorized clinical trial evaluating the potential of intravenously infused mesenchymal stem cells in adult Crohn's disease patients. For full details, visit ClinicalTrials.gov. For questions or further information, email david@hopebio.org. RESEARCH REVIEW NEWS ABOUT IBD The recent FDA approval of vagus nerve stimulation for rheumatoid arthritis patients gives hope to others with immune-mediated diseases. We look forward to the day when trials are announced for IBD patients. Article Link: BUSINESS WIRE "Scientists have discovered that certain immune cells—called neutrophils—can start making a protein called DUOX2 that they usually do not produce. This surprise activity may be fueling gut inflammation in conditions like Crohn's disease and ulcerative colitis." Article Link: MEDICAL XPRESS University of British Columbia researchers are refining a targeted drug delivery system -- GlycoCaging -- that could avert the systemic side effects of steroids and other iBD medications. Article Link: GENENG NEWS New research highlights cuproptosis—a copper-triggered form of cell death—as a promising new treatment approach for IBD and colorectal cancer. Copper can both fuel and fight disease, depending on levels. By targeting this process, scientists hope to develop therapies that kill harmful cells, overcome treatment resistance, and improve patient outcomes. Article Link: MEDICAL NEWS NET Your Support Is Very Important! Thank you for supporting Propel a Cure! If you can get involved, please let us know. We would love to have you as a volunteer! If you'd like more information about Propel a Cure or have suggestions for topics you'd like to see covered in the next newsletter, please contact us at info@propelacure.org. We are convinced that together we can make a difference! info@propelacure.org | PropelaCure.org