/ en Fri, 16 Jan 26 11:39:11 -0500 /news/scientists-develop-molecules-may-treat-crohns-disease <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Corie Lok</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" class="datetime">January 16, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>The molecules mimic a gene variant that protects against Crohn’s, demonstrating a roadmap for using genetics to develop therapies for inflammatory bowel disease and other chronic inflammatory disorders.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Sarah C.P. Williams </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" title="Friday, January 16, 2026 - 11:39" class="datetime">January 16, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Graphic depicts a small molecule as a chemical structure bound to a larger molecule."> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Card9_image.jpg?h=54982e30&itok=H_kc9kOF 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Card9_image.jpg?h=54982e30&itok=g2WTDPU5 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Card9_image.jpg?h=54982e30&itok=gIlErfsj 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN" alt="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." title="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Rush et al. Cell. DOI: 10.1016/j.cell.2025.12.013 </div> <div class="media-caption__description"> ӳ����ý scientists designed molecules (pictured in teal) that can bind CARD9 (white with red and blue), a protein linked to inflammatory bowel disease. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2926/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" 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block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="font-family:Open Sans;background-color:#f3f3f3;padding:2em;margin-bottom:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Scientists developed small molecules that target a protective gene variant strongly associated with inflammatory bowel disease.</li> <li aria-level="1">The compounds reduced both inflammatory signaling in human immune cells and inflammation in a mouse model.</li> <li aria-level="1">This human genetics-to-therapeutics pipeline can be applied to other diseases and challenging drug targets.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related News</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CIP-DEL_main3.jpg?itok=5_cUJ2DP 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k" alt="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." title="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Researchers devise new way to target and correct disease-related proteins</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/edited_rnf168.png?h=4252d3b7&itok=VUWOr-PB 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B" alt="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." title="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Single-cell analysis of Crohn’s disease reveals a detailed picture of inflammation in the gut</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>An estimated 3 million Americans have an inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis. But a lucky few individuals are far less likely to develop IBD because they have a rare variant of a gene called <em>CARD9</em>. This protective gene variant prevents the long-term digestive tract inflammation that can cause tissue damage and lead to disease.</p> <p>Now, researchers at the ӳ����ý, Mass General Brigham, Harvard Medical School, and Johnson & Johnson Innovative Medicine have developed small-molecule drug candidates that mimic the effects of this rare gene variant and could potentially treat Crohn’s and other inflammatory bowel diseases.</p> <p>The protective <em>CARD9 </em>variant was first identified by ӳ����ý researchers in 2011, who then discovered in 2015 how it worked to reduce IBD risk. The new study, published in <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank"><em>Cell</em></a>, reveals a set of molecules that have the same effect as the protective variant and decrease sustained inflammation in mice. The work demonstrates a complete genetics-to-therapeutics pipeline—from the initial discovery of a protective gene variant to the design of molecules that reproduce its beneficial effects.</p> <p>“The deep investments in human genetics are starting to pay off,” said study senior author <a href="/bios/ramnik-xavier">Ramnik Xavier</a>. “This study shows we can translate genetic insights about disease all the way to new drug candidates.”</p> <p>Xavier is a ӳ����ý core institute member, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital.</p> <p>The new study offers a roadmap for how to systematically translate genetic discoveries into new medicines. While this work took more than a decade, the team says similar efforts in the future can be accelerated thanks to new technologies such as gene editing in cells and disease models, novel chemistry approaches, and AI in drug discovery.</p> <p>“The genetics-to-therapeutics approach demonstrated in this CARD9 work is the full realization of the promise, and ultimate purpose, of our work in human genetics. This paradigm can and should be applied to other diseases where genetics has now identified causal genes and mechanisms,” said <a href="/bios/mark-daly">Mark Daly</a>, co-director of the Program in Medical and Population Genetics at the ӳ����ý and an institute member who led the 2011 research that identified IBD genes including <em>CARD9</em>.</p> <p>Daly is also the founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital and a professor at the Harvard Medical School.</p> <p>The study’s first authors are Jason Rush of the Center for the Development of Therapeutics at ӳ����ý, and Joshua Wertheimer and Steven Goldberg of Johnson & Johnson Innovative Medicine.</p> <h2>Genetics first</h2> <p>In 2011, Daly, Xavier, and colleagues <a href="https://www.nature.com/articles/ng.952" target="_blank">sequenced the genomes of tens of thousands of people with or without Crohn’s disease or ulcerative colitis</a>. The team identified dozens of genes linked to the conditions, including CARD9, which is known to be involved in inflammatory responses. People who had one common variant of CARD9 had an increased risk of developing IBD, while those with a rarer variant that truncated the protein were protected from the disease.</p> <p>But translating this genetic discovery into a drug was far from straightforward. Completely shutting off the function of the CARD9 protein would prevent the immune system from fighting infections in the gut. The protective variant somehow allowed this initial immune response while blocking longer-term inflammation. Moreover, CARD9 is what scientists call an “undruggable” target—a scaffolding protein with no obvious binding pockets for small molecules.</p> <p>Before attempting drug discovery, Xavier’s team first needed to understand exactly how the protective variant worked and which sections of the CARD9 protein were most important. In 2015, they <a href="https://www.cell.com/immunity/fulltext/S1074-7613(15)00405-7" target="_blank">published data</a> showing how the protective, shortened version of CARD9 acted like a brake on inflammation. They now knew which section of the protein—a so-called coiled-coil domain—must be targeted with a drug. </p> <p>“This work underscores how important it is to understand the nuanced biology of a protein before we target it with new drugs,” said <a href="/bios/daniel-graham">Daniel Graham</a>, a co-author on the latest study, and senior director of functional genomics in the Infectious Disease and Microbiome Program at the ӳ����ý, where he is also an institute scientist. “The old perspective of immediately trying to develop an activator or inhibitor isn’t going to serve us well with targets emerging from genetics.”</p> <h2>Screen time</h2> <p>In the new study, Xavier and his colleagues worked closely with Johnson & Johnson's Janssen research division to tackle the drug discovery challenge. They began with a massive screen of 20 billion molecules, searching for any compound that could bind to CARD9. The initial molecules they found didn’t have an impact on inflammation.</p> <p>Rather than abandoning the project, the team developed a tool to forge ahead. They obtained the first-ever crystal structure of CARD9 that showed how a small molecule could bind to a coiled-coil domain, confirming that they were targeting the right place on CARD9. Then, they converted one of the binding molecules into a fluorescent probe and tested additional compounds from Janssen's library—this time looking for molecules that pushed the fluorescent probe out of the way and bind to CARD9 in its place.</p> <p>Xavier said that using this “binder-first” approach was key to the team’s success. They pinpointed a new class of molecules that successfully blocked CARD9’s inflammatory signaling.</p> <p>“The binder-first strategy gave us two critical pieces of information,” said Xavier. “It proved CARD9 was druggable and gave us a clearer picture of where the precise binding site was on the coiled-coil domain. That allowed us to narrow our search and find molecules that actually work.”</p> <p>In human immune cells, the new molecules selectively reduced inflammatory signaling without affecting other immune pathways. In mice with the human CARD9 gene, treatment with the drug candidates reduced inflammation. </p> <h2>Roadmap for the future</h2> <p>While the new compounds require additional optimization before they can be tested in humans, the work demonstrates a complete pipeline from genetic discovery to therapeutic candidates. </p> <p>Xavier’s group is continuing to develop the new set of compounds starting with mechanistic validation of human genetics and explore their potential as therapies for patients with immune-mediated disease. Because the protective <em>CARD9 </em>variant exists in humans without causing problems, the researchers are optimistic about the safety profile of drugs that mimic its effects.</p> <p>“This is similar to the PCSK9 story for cholesterol drugs,” said Xavier, referring to a now-commonly prescribed class of drug that mimics the effects of a variant of the <em>PCSK9 </em>gene, which is linked to low cholesterol levels and reduced heart disease risk. “This hard-to-drug protective variant gave us the blueprint and the confidence that targeting this pathway can be done safely.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited:</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rush, J.S., et al. <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank">Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity</a>. <em>Cell</em>. Online January 16, 2026. DOI: 10.1016/j.cell.2025.12.013</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/inflammatory-bowel-disease-0" hreflang="en">Inflammatory bowel disease</a></div> <div class="field__item"><a href="/broad-tags/immunological-disease" hreflang="en">Immunological Disease</a></div> <div class="field__item"><a href="/broad-tags/small-molecules" hreflang="en">Small Molecules</a></div> <div class="field__item"><a href="/broad-tags/therapeutic-response" hreflang="en">Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/mark-daly" hreflang="en">Mark Daly</a></div> <div class="field__item"><a href="/broad-tags/ramnik-xavier" hreflang="en">Ramnik Xavier</a></div> </div> </div> </div> </div> </div> Fri, 16 Jan 2026 16:39:11 +0000 Corie Lok 5560116 at /news/scientists-discover-network-cells-and-genes-involved-crohns-disease-complication-0 <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Corie Lok</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" class="datetime">January 16, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>The molecules mimic a gene variant that protects against Crohn’s, demonstrating a roadmap for using genetics to develop therapies for inflammatory bowel disease and other chronic inflammatory disorders.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Sarah C.P. Williams </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" title="Friday, January 16, 2026 - 11:39" class="datetime">January 16, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Graphic depicts a small molecule as a chemical structure bound to a larger molecule."> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Card9_image.jpg?h=54982e30&itok=H_kc9kOF 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Card9_image.jpg?h=54982e30&itok=g2WTDPU5 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Card9_image.jpg?h=54982e30&itok=gIlErfsj 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN" alt="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." title="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Rush et al. Cell. DOI: 10.1016/j.cell.2025.12.013 </div> <div class="media-caption__description"> ӳ����ý scientists designed molecules (pictured in teal) that can bind CARD9 (white with red and blue), a protein linked to inflammatory bowel disease. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2926/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" 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block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="font-family:Open Sans;background-color:#f3f3f3;padding:2em;margin-bottom:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Scientists developed small molecules that target a protective gene variant strongly associated with inflammatory bowel disease.</li> <li aria-level="1">The compounds reduced both inflammatory signaling in human immune cells and inflammation in a mouse model.</li> <li aria-level="1">This human genetics-to-therapeutics pipeline can be applied to other diseases and challenging drug targets.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related News</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CIP-DEL_main3.jpg?itok=5_cUJ2DP 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k" alt="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." title="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Researchers devise new way to target and correct disease-related proteins</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/edited_rnf168.png?h=4252d3b7&itok=VUWOr-PB 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B" alt="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." title="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Single-cell analysis of Crohn’s disease reveals a detailed picture of inflammation in the gut</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>An estimated 3 million Americans have an inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis. But a lucky few individuals are far less likely to develop IBD because they have a rare variant of a gene called <em>CARD9</em>. This protective gene variant prevents the long-term digestive tract inflammation that can cause tissue damage and lead to disease.</p> <p>Now, researchers at the ӳ����ý, Mass General Brigham, Harvard Medical School, and Johnson & Johnson Innovative Medicine have developed small-molecule drug candidates that mimic the effects of this rare gene variant and could potentially treat Crohn’s and other inflammatory bowel diseases.</p> <p>The protective <em>CARD9 </em>variant was first identified by ӳ����ý researchers in 2011, who then discovered in 2015 how it worked to reduce IBD risk. The new study, published in <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank"><em>Cell</em></a>, reveals a set of molecules that have the same effect as the protective variant and decrease sustained inflammation in mice. The work demonstrates a complete genetics-to-therapeutics pipeline—from the initial discovery of a protective gene variant to the design of molecules that reproduce its beneficial effects.</p> <p>“The deep investments in human genetics are starting to pay off,” said study senior author <a href="/bios/ramnik-xavier">Ramnik Xavier</a>. “This study shows we can translate genetic insights about disease all the way to new drug candidates.”</p> <p>Xavier is a ӳ����ý core institute member, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital.</p> <p>The new study offers a roadmap for how to systematically translate genetic discoveries into new medicines. While this work took more than a decade, the team says similar efforts in the future can be accelerated thanks to new technologies such as gene editing in cells and disease models, novel chemistry approaches, and AI in drug discovery.</p> <p>“The genetics-to-therapeutics approach demonstrated in this CARD9 work is the full realization of the promise, and ultimate purpose, of our work in human genetics. This paradigm can and should be applied to other diseases where genetics has now identified causal genes and mechanisms,” said <a href="/bios/mark-daly">Mark Daly</a>, co-director of the Program in Medical and Population Genetics at the ӳ����ý and an institute member who led the 2011 research that identified IBD genes including <em>CARD9</em>.</p> <p>Daly is also the founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital and a professor at the Harvard Medical School.</p> <p>The study’s first authors are Jason Rush of the Center for the Development of Therapeutics at ӳ����ý, and Joshua Wertheimer and Steven Goldberg of Johnson & Johnson Innovative Medicine.</p> <h2>Genetics first</h2> <p>In 2011, Daly, Xavier, and colleagues <a href="https://www.nature.com/articles/ng.952" target="_blank">sequenced the genomes of tens of thousands of people with or without Crohn’s disease or ulcerative colitis</a>. The team identified dozens of genes linked to the conditions, including CARD9, which is known to be involved in inflammatory responses. People who had one common variant of CARD9 had an increased risk of developing IBD, while those with a rarer variant that truncated the protein were protected from the disease.</p> <p>But translating this genetic discovery into a drug was far from straightforward. Completely shutting off the function of the CARD9 protein would prevent the immune system from fighting infections in the gut. The protective variant somehow allowed this initial immune response while blocking longer-term inflammation. Moreover, CARD9 is what scientists call an “undruggable” target—a scaffolding protein with no obvious binding pockets for small molecules.</p> <p>Before attempting drug discovery, Xavier’s team first needed to understand exactly how the protective variant worked and which sections of the CARD9 protein were most important. In 2015, they <a href="https://www.cell.com/immunity/fulltext/S1074-7613(15)00405-7" target="_blank">published data</a> showing how the protective, shortened version of CARD9 acted like a brake on inflammation. They now knew which section of the protein—a so-called coiled-coil domain—must be targeted with a drug. </p> <p>“This work underscores how important it is to understand the nuanced biology of a protein before we target it with new drugs,” said <a href="/bios/daniel-graham">Daniel Graham</a>, a co-author on the latest study, and senior director of functional genomics in the Infectious Disease and Microbiome Program at the ӳ����ý, where he is also an institute scientist. “The old perspective of immediately trying to develop an activator or inhibitor isn’t going to serve us well with targets emerging from genetics.”</p> <h2>Screen time</h2> <p>In the new study, Xavier and his colleagues worked closely with Johnson & Johnson's Janssen research division to tackle the drug discovery challenge. They began with a massive screen of 20 billion molecules, searching for any compound that could bind to CARD9. The initial molecules they found didn’t have an impact on inflammation.</p> <p>Rather than abandoning the project, the team developed a tool to forge ahead. They obtained the first-ever crystal structure of CARD9 that showed how a small molecule could bind to a coiled-coil domain, confirming that they were targeting the right place on CARD9. Then, they converted one of the binding molecules into a fluorescent probe and tested additional compounds from Janssen's library—this time looking for molecules that pushed the fluorescent probe out of the way and bind to CARD9 in its place.</p> <p>Xavier said that using this “binder-first” approach was key to the team’s success. They pinpointed a new class of molecules that successfully blocked CARD9’s inflammatory signaling.</p> <p>“The binder-first strategy gave us two critical pieces of information,” said Xavier. “It proved CARD9 was druggable and gave us a clearer picture of where the precise binding site was on the coiled-coil domain. That allowed us to narrow our search and find molecules that actually work.”</p> <p>In human immune cells, the new molecules selectively reduced inflammatory signaling without affecting other immune pathways. In mice with the human CARD9 gene, treatment with the drug candidates reduced inflammation. </p> <h2>Roadmap for the future</h2> <p>While the new compounds require additional optimization before they can be tested in humans, the work demonstrates a complete pipeline from genetic discovery to therapeutic candidates. </p> <p>Xavier’s group is continuing to develop the new set of compounds starting with mechanistic validation of human genetics and explore their potential as therapies for patients with immune-mediated disease. Because the protective <em>CARD9 </em>variant exists in humans without causing problems, the researchers are optimistic about the safety profile of drugs that mimic its effects.</p> <p>“This is similar to the PCSK9 story for cholesterol drugs,” said Xavier, referring to a now-commonly prescribed class of drug that mimics the effects of a variant of the <em>PCSK9 </em>gene, which is linked to low cholesterol levels and reduced heart disease risk. “This hard-to-drug protective variant gave us the blueprint and the confidence that targeting this pathway can be done safely.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited:</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rush, J.S., et al. <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank">Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity</a>. <em>Cell</em>. Online January 16, 2026. DOI: 10.1016/j.cell.2025.12.013</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/inflammatory-bowel-disease-0" hreflang="en">Inflammatory bowel disease</a></div> <div class="field__item"><a href="/broad-tags/immunological-disease" hreflang="en">Immunological Disease</a></div> <div class="field__item"><a href="/broad-tags/small-molecules" hreflang="en">Small Molecules</a></div> <div class="field__item"><a href="/broad-tags/therapeutic-response" hreflang="en">Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/mark-daly" hreflang="en">Mark Daly</a></div> <div class="field__item"><a href="/broad-tags/ramnik-xavier" hreflang="en">Ramnik Xavier</a></div> </div> </div> </div> </div> </div> Wed, 25 Jun 2025 09:00:10 +0000 adicorat 5558796 at /news/whyiscience-qa-microbiologist-and-immunologist-finds-links-between-our-own-microbes-and <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Corie Lok</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" class="datetime">January 16, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>The molecules mimic a gene variant that protects against Crohn’s, demonstrating a roadmap for using genetics to develop therapies for inflammatory bowel disease and other chronic inflammatory disorders.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Sarah C.P. Williams </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" title="Friday, January 16, 2026 - 11:39" class="datetime">January 16, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Graphic depicts a small molecule as a chemical structure bound to a larger molecule."> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Card9_image.jpg?h=54982e30&itok=H_kc9kOF 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Card9_image.jpg?h=54982e30&itok=g2WTDPU5 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Card9_image.jpg?h=54982e30&itok=gIlErfsj 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN" alt="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." title="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Rush et al. Cell. DOI: 10.1016/j.cell.2025.12.013 </div> <div class="media-caption__description"> ӳ����ý scientists designed molecules (pictured in teal) that can bind CARD9 (white with red and blue), a protein linked to inflammatory bowel disease. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2926/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" 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block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="font-family:Open Sans;background-color:#f3f3f3;padding:2em;margin-bottom:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Scientists developed small molecules that target a protective gene variant strongly associated with inflammatory bowel disease.</li> <li aria-level="1">The compounds reduced both inflammatory signaling in human immune cells and inflammation in a mouse model.</li> <li aria-level="1">This human genetics-to-therapeutics pipeline can be applied to other diseases and challenging drug targets.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related News</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CIP-DEL_main3.jpg?itok=5_cUJ2DP 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k" alt="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." title="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Researchers devise new way to target and correct disease-related proteins</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/edited_rnf168.png?h=4252d3b7&itok=VUWOr-PB 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B" alt="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." title="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Single-cell analysis of Crohn’s disease reveals a detailed picture of inflammation in the gut</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>An estimated 3 million Americans have an inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis. But a lucky few individuals are far less likely to develop IBD because they have a rare variant of a gene called <em>CARD9</em>. This protective gene variant prevents the long-term digestive tract inflammation that can cause tissue damage and lead to disease.</p> <p>Now, researchers at the ӳ����ý, Mass General Brigham, Harvard Medical School, and Johnson & Johnson Innovative Medicine have developed small-molecule drug candidates that mimic the effects of this rare gene variant and could potentially treat Crohn’s and other inflammatory bowel diseases.</p> <p>The protective <em>CARD9 </em>variant was first identified by ӳ����ý researchers in 2011, who then discovered in 2015 how it worked to reduce IBD risk. The new study, published in <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank"><em>Cell</em></a>, reveals a set of molecules that have the same effect as the protective variant and decrease sustained inflammation in mice. The work demonstrates a complete genetics-to-therapeutics pipeline—from the initial discovery of a protective gene variant to the design of molecules that reproduce its beneficial effects.</p> <p>“The deep investments in human genetics are starting to pay off,” said study senior author <a href="/bios/ramnik-xavier">Ramnik Xavier</a>. “This study shows we can translate genetic insights about disease all the way to new drug candidates.”</p> <p>Xavier is a ӳ����ý core institute member, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital.</p> <p>The new study offers a roadmap for how to systematically translate genetic discoveries into new medicines. While this work took more than a decade, the team says similar efforts in the future can be accelerated thanks to new technologies such as gene editing in cells and disease models, novel chemistry approaches, and AI in drug discovery.</p> <p>“The genetics-to-therapeutics approach demonstrated in this CARD9 work is the full realization of the promise, and ultimate purpose, of our work in human genetics. This paradigm can and should be applied to other diseases where genetics has now identified causal genes and mechanisms,” said <a href="/bios/mark-daly">Mark Daly</a>, co-director of the Program in Medical and Population Genetics at the ӳ����ý and an institute member who led the 2011 research that identified IBD genes including <em>CARD9</em>.</p> <p>Daly is also the founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital and a professor at the Harvard Medical School.</p> <p>The study’s first authors are Jason Rush of the Center for the Development of Therapeutics at ӳ����ý, and Joshua Wertheimer and Steven Goldberg of Johnson & Johnson Innovative Medicine.</p> <h2>Genetics first</h2> <p>In 2011, Daly, Xavier, and colleagues <a href="https://www.nature.com/articles/ng.952" target="_blank">sequenced the genomes of tens of thousands of people with or without Crohn’s disease or ulcerative colitis</a>. The team identified dozens of genes linked to the conditions, including CARD9, which is known to be involved in inflammatory responses. People who had one common variant of CARD9 had an increased risk of developing IBD, while those with a rarer variant that truncated the protein were protected from the disease.</p> <p>But translating this genetic discovery into a drug was far from straightforward. Completely shutting off the function of the CARD9 protein would prevent the immune system from fighting infections in the gut. The protective variant somehow allowed this initial immune response while blocking longer-term inflammation. Moreover, CARD9 is what scientists call an “undruggable” target—a scaffolding protein with no obvious binding pockets for small molecules.</p> <p>Before attempting drug discovery, Xavier’s team first needed to understand exactly how the protective variant worked and which sections of the CARD9 protein were most important. In 2015, they <a href="https://www.cell.com/immunity/fulltext/S1074-7613(15)00405-7" target="_blank">published data</a> showing how the protective, shortened version of CARD9 acted like a brake on inflammation. They now knew which section of the protein—a so-called coiled-coil domain—must be targeted with a drug. </p> <p>“This work underscores how important it is to understand the nuanced biology of a protein before we target it with new drugs,” said <a href="/bios/daniel-graham">Daniel Graham</a>, a co-author on the latest study, and senior director of functional genomics in the Infectious Disease and Microbiome Program at the ӳ����ý, where he is also an institute scientist. “The old perspective of immediately trying to develop an activator or inhibitor isn’t going to serve us well with targets emerging from genetics.”</p> <h2>Screen time</h2> <p>In the new study, Xavier and his colleagues worked closely with Johnson & Johnson's Janssen research division to tackle the drug discovery challenge. They began with a massive screen of 20 billion molecules, searching for any compound that could bind to CARD9. The initial molecules they found didn’t have an impact on inflammation.</p> <p>Rather than abandoning the project, the team developed a tool to forge ahead. They obtained the first-ever crystal structure of CARD9 that showed how a small molecule could bind to a coiled-coil domain, confirming that they were targeting the right place on CARD9. Then, they converted one of the binding molecules into a fluorescent probe and tested additional compounds from Janssen's library—this time looking for molecules that pushed the fluorescent probe out of the way and bind to CARD9 in its place.</p> <p>Xavier said that using this “binder-first” approach was key to the team’s success. They pinpointed a new class of molecules that successfully blocked CARD9’s inflammatory signaling.</p> <p>“The binder-first strategy gave us two critical pieces of information,” said Xavier. “It proved CARD9 was druggable and gave us a clearer picture of where the precise binding site was on the coiled-coil domain. That allowed us to narrow our search and find molecules that actually work.”</p> <p>In human immune cells, the new molecules selectively reduced inflammatory signaling without affecting other immune pathways. In mice with the human CARD9 gene, treatment with the drug candidates reduced inflammation. </p> <h2>Roadmap for the future</h2> <p>While the new compounds require additional optimization before they can be tested in humans, the work demonstrates a complete pipeline from genetic discovery to therapeutic candidates. </p> <p>Xavier’s group is continuing to develop the new set of compounds starting with mechanistic validation of human genetics and explore their potential as therapies for patients with immune-mediated disease. Because the protective <em>CARD9 </em>variant exists in humans without causing problems, the researchers are optimistic about the safety profile of drugs that mimic its effects.</p> <p>“This is similar to the PCSK9 story for cholesterol drugs,” said Xavier, referring to a now-commonly prescribed class of drug that mimics the effects of a variant of the <em>PCSK9 </em>gene, which is linked to low cholesterol levels and reduced heart disease risk. “This hard-to-drug protective variant gave us the blueprint and the confidence that targeting this pathway can be done safely.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited:</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rush, J.S., et al. <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank">Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity</a>. <em>Cell</em>. Online January 16, 2026. DOI: 10.1016/j.cell.2025.12.013</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/inflammatory-bowel-disease-0" hreflang="en">Inflammatory bowel disease</a></div> <div class="field__item"><a href="/broad-tags/immunological-disease" hreflang="en">Immunological Disease</a></div> <div class="field__item"><a href="/broad-tags/small-molecules" hreflang="en">Small Molecules</a></div> <div class="field__item"><a href="/broad-tags/therapeutic-response" hreflang="en">Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/mark-daly" hreflang="en">Mark Daly</a></div> <div class="field__item"><a href="/broad-tags/ramnik-xavier" hreflang="en">Ramnik Xavier</a></div> </div> </div> </div> </div> </div> Tue, 15 Oct 2024 18:32:38 +0000 arinavetta 5557286 at /news/scientists-identify-unique-combination-bacterial-strains-could-treat-antibiotic-resistant-gut <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> <span class="field field--name-uid field--type-entity-reference field--label-hidden"> <span>By Corie Lok</span> </span> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" class="datetime">January 16, 2026</time> </span> <div class="hero-section container"> <div class="hero-section__row row"> <div class="hero-section__content hero-section__content_left col-6"> <div class="hero-section__breadcrumbs"> <div class="block block-system block-system-breadcrumb-block"> <nav class="breadcrumb" role="navigation" aria-labelledby="system-breadcrumb"> <h2 id="system-breadcrumb" class="visually-hidden">Breadcrumb</h2> <ol> <li> <a href="/">Home</a> </li> <li> <a href="/news">News</a> </li> </ol> </nav> </div> </div> <div class="hero-section__title"> <div class="block block-layout-builder block-field-blocknodelong-storytitle"> <span class="field field--name-title field--type-string field--label-hidden"><h1>Scientists develop molecules that may treat Crohn’s disease</h1> </span> </div> </div> <div class="hero-section__description"> <div class="block block-layout-builder block-field-blocknodelong-storybody"> <div class="clearfix text-formatted field field--name-body field--type-text-with-summary field--label-hidden field__item"><p>The molecules mimic a gene variant that protects against Crohn’s, demonstrating a roadmap for using genetics to develop therapies for inflammatory bowel disease and other chronic inflammatory disorders.</p> </div> </div> </div> <div class="hero-section__author"> <div class="block block-layout-builder block-extra-field-blocknodelong-storyextra-field-author-custom"> By Sarah C.P. Williams </div> </div> <div class="hero-section__date"> <div class="block block-layout-builder block-field-blocknodelong-storycreated"> <span class="field field--name-created field--type-created field--label-hidden"><time datetime="2026-01-16T11:39:11-05:00" title="Friday, January 16, 2026 - 11:39" class="datetime">January 16, 2026</time> </span> </div> </div> </div> <div class="hero-section__right col-6"> <div class="hero-section__image"> <div class="block block-layout-builder block-field-blocknodelong-storyfield-image"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"> <article class="media media--type-image media--view-mode-multiple-content-types-header"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Graphic depicts a small molecule as a chemical structure bound to a larger molecule."> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop_xl/public/longstory/Card9_image.jpg?h=54982e30&itok=DkxjOOCg 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="754" height="503"/> <source srcset="/files/styles/multiple_ct_header_desktop/public/longstory/Card9_image.jpg?h=54982e30&itok=H_kc9kOF 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="736" height="520"/> <source srcset="/files/styles/multiple_ct_header_laptop/public/longstory/Card9_image.jpg?h=54982e30&itok=g2WTDPU5 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="641" height="451"/> <source srcset="/files/styles/multiple_ct_header_tablet/public/longstory/Card9_image.jpg?h=54982e30&itok=gIlErfsj 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="706" height="417"/> <source srcset="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN 1x" media="all and (max-width: 539px)" type="image/jpeg" width="499" height="294"/> <img loading="eager" width="499" height="294" src="/files/styles/multiple_ct_header_phone/public/longstory/Card9_image.jpg?h=54982e30&itok=KOrY7-VN" alt="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." title="Graphic depicts a small molecule as a chemical structure bound to a larger molecule." typeof="foaf:Image" /> </picture> </div> <div class="media-caption"> <div class="media-caption__credit"> Credit: Rush et al. Cell. DOI: 10.1016/j.cell.2025.12.013 </div> <div class="media-caption__description"> ӳ����ý scientists designed molecules (pictured in teal) that can bind CARD9 (white with red and blue), a protein linked to inflammatory bowel disease. </div> </div> </article> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block block-better-social-sharing-buttons block-social-sharing-buttons-block"> <div style="display: none"><link rel="preload" href="/modules/contrib/better_social_sharing_buttons/assets/dist/sprites/social-icons--no-color.svg" as="image" type="image/svg+xml" crossorigin="anonymous" /></div> <div class="social-sharing-buttons"> <a href="https://www.facebook.com/sharer/sharer.php?u=/taxonomy/term/2926/feed&title=" target="_blank" title="Share to Facebook" aria-label="Share to Facebook" class="social-sharing-buttons-button share-facebook" rel="noopener"> <svg aria-hidden="true" width="32px" height="32px" 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block-layout-builder block-field-blocknodelong-storyfield-content-paragraphs"> <div class="field field--name-field-content-paragraphs field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--text-narrow paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><div class="clearfix" style="font-family:Open Sans;background-color:#f3f3f3;padding:2em;margin-bottom:2em;"> <h3>Highlights</h3> <ul> <li aria-level="1">Scientists developed small molecules that target a protective gene variant strongly associated with inflammatory bowel disease.</li> <li aria-level="1">The compounds reduced both inflammatory signaling in human immune cells and inflammation in a mouse model.</li> <li aria-level="1">This human genetics-to-therapeutics pipeline can be applied to other diseases and challenging drug targets.</li> </ul> </div> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--text-with-sidebar text-with-sidebar"> <div class="field field--name-field-sidebar field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--sidebar-articles sidebar-articles"> <div class="sidebar-articles__col"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Related News</p> </div> <div class="field field--name-field-content-reference field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><article about="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1921px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/longstory/CIP-DEL_main3.jpg?itok=zUCXn1v0 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/jpeg" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/longstory/CIP-DEL_main3.jpg?itok=CIWrX2ne 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/jpeg" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/longstory/CIP-DEL_main3.jpg?itok=5_cUJ2DP 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/jpeg" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k 1x" media="all and (max-width: 539px)" type="image/jpeg" width="220" height="186"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/longstory/CIP-DEL_main3.jpg?itok=Silyf8_k" alt="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." title="A graphical illustration of proteins and small molecules interacting, showing a larger protein in purple and a smaller one in dark green bound to a red hexagon and a light blue triangle element, with a short red double helix attached." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/researchers-devise-new-way-target-and-correct-disease-related-proteins" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Researchers devise new way to target and correct disease-related proteins</span> </a> </div> </article> </div> <div class="field__item"><article about="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node"> <div class="field field--name-field-image field--type-entity-reference field--label-hidden field__item"><article class="media media--type-image media--view-mode-multiple-ct-sidebar-link-with-image"> <div class="field field--name-field-media-image field--type-image field--label-hidden field__item"> <picture role="img" aria-label="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production."> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1921px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop_xl/public/edited_rnf168.png?h=4252d3b7&itok=3QziMCnn 1x" media="all and (min-width: 1601px) and (max-width: 1920px)" type="image/png" width="104" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 1340px) and (max-width: 1600px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_desktop/public/edited_rnf168.png?h=4252d3b7&itok=INl2fFXN 1x" media="all and (min-width: 800px) and (max-width: 1339px)" type="image/png" width="87" height="104"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_tablet/public/edited_rnf168.png?h=4252d3b7&itok=VUWOr-PB 1x" media="all and (min-width: 540px) and (max-width: 799px)" type="image/png" width="285" height="186"> <source srcset="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B 1x" media="all and (max-width: 539px)" type="image/png" width="220" height="186"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut"><img loading="eager" width="220" height="186" src="/files/styles/multiple_ct_sidebar_link_with_image_phone/public/edited_rnf168.png?h=4252d3b7&itok=QSP10w2B" alt="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." title="Collagen (green) and cell nuclei (blue) in fibroblasts with knockdown of the gene RNF168, which affects collagen production." typeof="foaf:Image"></a> </picture> </div> </article> </div> <div class="node__content"> <a href="/news/single-cell-analysis-crohns-disease-reveals-detailed-picture-inflammation-gut" class="node__title"><span class="field field--name-title field--type-string field--label-hidden">Single-cell analysis of Crohn’s disease reveals a detailed picture of inflammation in the gut</span> </a> </div> </article> </div> </div> </div> </div> </div> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>An estimated 3 million Americans have an inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis. But a lucky few individuals are far less likely to develop IBD because they have a rare variant of a gene called <em>CARD9</em>. This protective gene variant prevents the long-term digestive tract inflammation that can cause tissue damage and lead to disease.</p> <p>Now, researchers at the ӳ����ý, Mass General Brigham, Harvard Medical School, and Johnson & Johnson Innovative Medicine have developed small-molecule drug candidates that mimic the effects of this rare gene variant and could potentially treat Crohn’s and other inflammatory bowel diseases.</p> <p>The protective <em>CARD9 </em>variant was first identified by ӳ����ý researchers in 2011, who then discovered in 2015 how it worked to reduce IBD risk. The new study, published in <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank"><em>Cell</em></a>, reveals a set of molecules that have the same effect as the protective variant and decrease sustained inflammation in mice. The work demonstrates a complete genetics-to-therapeutics pipeline—from the initial discovery of a protective gene variant to the design of molecules that reproduce its beneficial effects.</p> <p>“The deep investments in human genetics are starting to pay off,” said study senior author <a href="/bios/ramnik-xavier">Ramnik Xavier</a>. “This study shows we can translate genetic insights about disease all the way to new drug candidates.”</p> <p>Xavier is a ӳ����ý core institute member, the Kurt J. Isselbacher Professor of Medicine at Harvard Medical School, and director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Massachusetts General Hospital.</p> <p>The new study offers a roadmap for how to systematically translate genetic discoveries into new medicines. While this work took more than a decade, the team says similar efforts in the future can be accelerated thanks to new technologies such as gene editing in cells and disease models, novel chemistry approaches, and AI in drug discovery.</p> <p>“The genetics-to-therapeutics approach demonstrated in this CARD9 work is the full realization of the promise, and ultimate purpose, of our work in human genetics. This paradigm can and should be applied to other diseases where genetics has now identified causal genes and mechanisms,” said <a href="/bios/mark-daly">Mark Daly</a>, co-director of the Program in Medical and Population Genetics at the ӳ����ý and an institute member who led the 2011 research that identified IBD genes including <em>CARD9</em>.</p> <p>Daly is also the founding chief of the Analytic and Translational Genetics Unit at Massachusetts General Hospital and a professor at the Harvard Medical School.</p> <p>The study’s first authors are Jason Rush of the Center for the Development of Therapeutics at ӳ����ý, and Joshua Wertheimer and Steven Goldberg of Johnson & Johnson Innovative Medicine.</p> <h2>Genetics first</h2> <p>In 2011, Daly, Xavier, and colleagues <a href="https://www.nature.com/articles/ng.952" target="_blank">sequenced the genomes of tens of thousands of people with or without Crohn’s disease or ulcerative colitis</a>. The team identified dozens of genes linked to the conditions, including CARD9, which is known to be involved in inflammatory responses. People who had one common variant of CARD9 had an increased risk of developing IBD, while those with a rarer variant that truncated the protein were protected from the disease.</p> <p>But translating this genetic discovery into a drug was far from straightforward. Completely shutting off the function of the CARD9 protein would prevent the immune system from fighting infections in the gut. The protective variant somehow allowed this initial immune response while blocking longer-term inflammation. Moreover, CARD9 is what scientists call an “undruggable” target—a scaffolding protein with no obvious binding pockets for small molecules.</p> <p>Before attempting drug discovery, Xavier’s team first needed to understand exactly how the protective variant worked and which sections of the CARD9 protein were most important. In 2015, they <a href="https://www.cell.com/immunity/fulltext/S1074-7613(15)00405-7" target="_blank">published data</a> showing how the protective, shortened version of CARD9 acted like a brake on inflammation. They now knew which section of the protein—a so-called coiled-coil domain—must be targeted with a drug. </p> <p>“This work underscores how important it is to understand the nuanced biology of a protein before we target it with new drugs,” said <a href="/bios/daniel-graham">Daniel Graham</a>, a co-author on the latest study, and senior director of functional genomics in the Infectious Disease and Microbiome Program at the ӳ����ý, where he is also an institute scientist. “The old perspective of immediately trying to develop an activator or inhibitor isn’t going to serve us well with targets emerging from genetics.”</p> <h2>Screen time</h2> <p>In the new study, Xavier and his colleagues worked closely with Johnson & Johnson's Janssen research division to tackle the drug discovery challenge. They began with a massive screen of 20 billion molecules, searching for any compound that could bind to CARD9. The initial molecules they found didn’t have an impact on inflammation.</p> <p>Rather than abandoning the project, the team developed a tool to forge ahead. They obtained the first-ever crystal structure of CARD9 that showed how a small molecule could bind to a coiled-coil domain, confirming that they were targeting the right place on CARD9. Then, they converted one of the binding molecules into a fluorescent probe and tested additional compounds from Janssen's library—this time looking for molecules that pushed the fluorescent probe out of the way and bind to CARD9 in its place.</p> <p>Xavier said that using this “binder-first” approach was key to the team’s success. They pinpointed a new class of molecules that successfully blocked CARD9’s inflammatory signaling.</p> <p>“The binder-first strategy gave us two critical pieces of information,” said Xavier. “It proved CARD9 was druggable and gave us a clearer picture of where the precise binding site was on the coiled-coil domain. That allowed us to narrow our search and find molecules that actually work.”</p> <p>In human immune cells, the new molecules selectively reduced inflammatory signaling without affecting other immune pathways. In mice with the human CARD9 gene, treatment with the drug candidates reduced inflammation. </p> <h2>Roadmap for the future</h2> <p>While the new compounds require additional optimization before they can be tested in humans, the work demonstrates a complete pipeline from genetic discovery to therapeutic candidates. </p> <p>Xavier’s group is continuing to develop the new set of compounds starting with mechanistic validation of human genetics and explore their potential as therapies for patients with immune-mediated disease. Because the protective <em>CARD9 </em>variant exists in humans without causing problems, the researchers are optimistic about the safety profile of drugs that mimic its effects.</p> <p>“This is similar to the PCSK9 story for cholesterol drugs,” said Xavier, referring to a now-commonly prescribed class of drug that mimics the effects of a variant of the <em>PCSK9 </em>gene, which is linked to low cholesterol levels and reduced heart disease risk. “This hard-to-drug protective variant gave us the blueprint and the confidence that targeting this pathway can be done safely.”</p> </div> </div> </div> <div class="field__item"> <div class="paragraph paragraph--type--table-outro paragraph--view-mode--default"> <div class="field field--name-field-paragraph field--type-entity-reference-revisions field--label-hidden field__items"> <div class="field__item"> <div class="paragraph paragraph--type--table-outro-row paragraph--view-mode--default"> <div class="clearfix text-formatted field field--name-field-heading field--type-text field--label-hidden field__item"><p>Paper cited:</p> </div> <div class="clearfix text-formatted field field--name-field-text field--type-text-long field--label-hidden field__item"><p>Rush, J.S., et al. <a href="https://www.cell.com/cell/fulltext/S0092-8674(25)01426-6" target="_blank">Human genetics guides the discovery of CARD9 inhibitors with anti-inflammatory activity</a>. <em>Cell</em>. Online January 16, 2026. DOI: 10.1016/j.cell.2025.12.013</p> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> <div class="content-section container"> <div class="content-section__main"> <div class="block-node-broad-tags block block-layout-builder block-field-blocknodelong-storyfield-broad-tags"> <div class="block-node-broad-tags__row"> <div class="block-node-broad-tags__title">Tags:</div> <div class="field field--name-field-broad-tags field--type-entity-reference field--label-hidden field__items"> <div class="field__item"><a href="/broad-tags/inflammatory-bowel-disease-0" hreflang="en">Inflammatory bowel disease</a></div> <div class="field__item"><a href="/broad-tags/immunological-disease" hreflang="en">Immunological Disease</a></div> <div class="field__item"><a href="/broad-tags/small-molecules" hreflang="en">Small Molecules</a></div> <div class="field__item"><a href="/broad-tags/therapeutic-response" hreflang="en">Therapeutics</a></div> <div class="field__item"><a href="/broad-tags/mark-daly" hreflang="en">Mark Daly</a></div> <div class="field__item"><a href="/broad-tags/ramnik-xavier" hreflang="en">Ramnik Xavier</a></div> </div> </div> </div> </div> </div> Wed, 18 Sep 2024 14:51:33 +0000 adicorat 5557391 at