At a glance
Scientists developed small molecules that mimic a genetic variant associated with protection against inflammatory bowel disease.
The molecules reduced signs of inflammation in human immune cells and in a mouse model.
The methods they used to move from human genetics to potential drugs can be applied to other diseases and challenging drug targets.
An estimated 3 million Americans have an inflammatory bowel disease (IBD) such as Crohn’s disease or ulcerative colitis. But a lucky few are far less likely to develop IBD because they have a rare variant of a gene called CARD9. This protective gene variant prevents the long-term digestive tract inflammation that can cause tissue damage and lead to disease.
Now, researchers at the Broad Institute of MIT and Harvard, Massachusetts General Hospital, Harvard Medical School, and Johnson & Johnson Innovative Medicine have developed small molecules that mimic the protection of this rare gene variant in human cells and mouse models. If further-improved versions of the molecules prove safe and effective in clinical trials, they could be used as medicines to treat Crohn’s and other inflammatory bowel diseases.
The study, published Jan. 16 in Cell, offers a road map for how to systematically translate genetic discoveries into new medicines.
“The deep investments in human genetics are starting to pay off,” said senior author Ramnik Xavier, the HMS Kurt J. Isselbacher Professor of Medicine in the Field of Gastroenterology at Mass General and a Broad Institute core member. “This study shows we can translate genetic insights about disease all the way to new drug candidates.”
While the project took more than a decade, the team says future efforts can be accelerated thanks to new technologies such as gene-editing variants in cells and disease models, novel chemistry approaches, and AI in drug discovery.
“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,” said Mark Daly, HMS associate professor of medicine at Mass General and co-director of the Program in Medical and Population Genetics at the Broad Institute. “This paradigm can and should be applied to other diseases where genetics has now identified causal genes and mechanisms.”
From genetics to therapeutics
Xavier, Daly, and colleagues first identified the protective CARD9 variant in 2011. But translating that discovery into a drug was far from straightforward. For one thing, completely shutting off the function of the CARD9 protein would prevent the immune system from fighting infections in the gut. Moreover, CARD9 is what scientists call an “undruggable” target — it has no obvious pockets for small-molecule drugs to bind.
In 2015, the team revealed how the variant works to reduce IBD risk. That showed which section of the protein needed to be targeted with a drug.
The new study built on that knowledge. Xavier and colleagues, working closely with Johnson & Johnson’s Janssen research division, screened 20 billion molecules for anything that could bind to the CARD9 protein. When the initial matches didn’t have an impact on inflammation, 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 the right section of it. They converted one of those molecules into a probe. They were then able to screen Janssen’s library for molecules that pushed the probe out of the way and bound to CARD9 in its place — blocking CARD9’s inflammatory signaling.
Xavier said that using this “binder-first” approach was key to the team’s success.
“It proved CARD9 was druggable and gave us a clearer picture of where the precise binding site was,” he said. “That allowed us to narrow our search and find molecules that actually work.”
The new molecules selectively reduced inflammatory signaling in human immune cells without affecting other immune pathways. Treatment with the molecules also reduced inflammation in mice with the human CARD9 gene.
The team’s method demonstrates the value of learning the biological mechanisms involved in a disease when trying to develop a drug based on a genetic insight.
“This work underscores how important it is to understand the nuanced biology of a protein before we target it with new drugs,” said co-author Daniel Graham, HMS instructor in medicine at Mass General and a Broad 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.”
Adapted from a Broad Institute news release.
Authorship, funding, disclosures
Jason Rush, Joshua Wertheimer, and Steven Goldberg are co-first authors of the study. Additional authors include Donald Raymond, Mateusz Szuchnicki, Andrew J. Baltus, Jeff Branson, Christopher F. Stratton, Aaron N. Patrick, Ruth Steele, Suraj Adhikary, Amanda Del Rosario, Annie Liu, Noah J. Gomersall, Michael Chung, Matthew J. Ranaghan, Xiebin Gu, Marta Brandt, Zhifang Cao, Adrian Bebenek, Blayne A. Oliver, Kasper Hoebe, Lawrence M. Szewczuk, Jennifer D. Venable, Daniel B. Graham, and Jennifer Towne. Xavier is also director of the Center for Computational and Integrative Biology and core member in the Department of Molecular Biology at Mass General.
This work was funded by Janssen, the National Institutes of Health (grant R01AI137325), and The Leona M. and Harry B. Helmsley Charitable Trust.
Xavier is board director at MoonLake Immunotherapeutics, co-founder of Convergence Bio, consultant to Nestlé, and a member of the scientific advisory board at Magnet Biomedicine; these organizations had no roles in this study.
