Preclinical Research That Relates to Human Disease
Before scientists can develop new treatments for IBD, they need to understand more about why disease occurs and how it progresses. “Preclinical” research, which is laboratory-based research, sets the stage for future studies that might involve testing on patients.
While we fund many preclinical research projects that scientists bring to our attention, we also identify priority areas where we ask researchers to bring us projects focused on specific topics. We are currently funding two specific areas in preclinical research through our Genetics and Fibrosis initiatives.
Genetics Initiative
The Genetics Initiative is the Foundation’s ongoing project that explores how a person’s genes contribute to IBD. A major goal is to find gene-controlled pathways—a series of biochemical reactions inside and across cells—that may play a role in the development or progression of IBD. Identifying these pathways may help us identify or develop new medications that can stop a negative chain reaction or promote a positive one and potentially lead to remission or cure.
Thanks to years of investment in this area, scientists have already identified hundreds of genetic mutations (changes in genes) associated with IBD. We’re still learning more about which genes are most important, as well as what might cause the genes to be turned on (or off) and lead to IBD in people who are at risk for it or lead to more serious disease among those living with IBD.
One major finding, from researchers at Massachusetts General Hospital and the Broad Institute, is the discovery of the mechanisms by which the C1orf106 gene may lead to ulcerative colitis. C1orf106 is a gene that, when mutated, raises the risk of developing ulcerative colitis. In healthy people, the cells that make up the intestinal wall stay tightly connected to one another thanks to “adherens junctions,” which are proteins that serve as the glue between the cells that line the gut.
A strong intestinal wall, fortified by these junctions, forms a barrier that prevents harmful bacteria and viruses from reaching the inner lining of the intestine. In people with IBD, however, these junctions are often not properly assembled or are missing, which results in inflammation and damage to the lining of the intestinal wall. Ongoing research aims to understand why these junctions are compromised so we can attempt to develop new treatments that would prevent or undo this problem. Our goal isn't just to improve symptoms but to restore the intestinal barrier and healthy functioning of the intestinal wall.
Meanwhile, another Genetics Initiative project, led by researchers at the Cleveland Clinic Foundation, is focused on understanding the role of the serpin1 gene that produces a protein called PAI-1 (plasminogen activator inhibitor). Scientists discovered that high levels of both serpin1 and PAI-1 interfere with gut healing by blocking a clot-dissolving protein called TPA (tissue plasminogen activator). They determined that gut ulcers often do not heal in people with IBD because of excess PAI-1.
If they can figure out how to block PAI-1, then the clot-dissolving protein TPA can do its job and make it possible for normal tissue repair to continue. They also demonstrated that reducing the activity of PAI-1 using a drug-like inhibitor of PAI-1, improved colitis and induced restoration of the intestinal wall in pre-clinical models of IBD.
Inspired by these results, the Crohn’s & Colitis Foundation envisioned the creation of a research partnership to accelerate the discovery of novel safe PAI-1 inhibitors that would work only within the gut. This “therapeutics incubator”— a three-way collaboration between the Foundation, the Cleveland Clinic, and Evotec (a specialized drug discovery company) has since led to the development of a compound that blocks PAI-1, decreases inflammation in the gut, and induces mucosal healing (heals the intestinal wall). This compound stays within the intestine and does not reach the high levels in the blood stream, which helps to minimize side effects. The team is currently in the process of refining and testing this compound and hopes to move to clinical trials within a few years.
The Foundation is also working with the Welcome Sanger Institute in the UK to implement novel state-of-the-art genetics technologies that will provide more information about the role of IBD genes in the different cell types that are found in the gut. This presents the opportunity to better understand the role of genes in IBD and the potential to develop targeted approaches to treat the disease. By targeting the exact genes and exact cells driving pathology, this could lead to new treatments with increased effectiveness and decreased side effects.
Fibrosis Initiative
The Fibrosis Initiative is an ongoing study that aims to reveal why certain IBD patients develop fibrosis, which is a buildup of scar tissue in the gut that can cause intestinal blockages (strictures) and often requires surgical removal. This research should pave the way for the development of new methods to prevent and treat fibrosis.
Scientists believe that complications like fibrosis don’t happen randomly. Instead, specific genetic mutations and defective proteins, together with environmental factors likely explain how the disease will progress in a particular patient. The Foundation is currently funding work at Cedars-Sinai Medical Center in Los Angeles that uses state-of-the-art stem cell technology to transform blood samples from IBD patients and turn them into three-dimensional “mini guts.” These mini guts are derived from blood samples from IBD patients that are stored at an extensive Cedars-Sinai biobank (a storage unit for biologic materials).
Homing in on the differences between the mini-guts that came from patients with and without fibrosis will enable us to learn more about who is most likely to develop fibrosis and which genes and other factors, like gut microbes, might play a role in its development. The mini-gut models can also be used to screen, identify, and test new drug candidates (new treatments) in a lab setting before testing them on humans.
A proof of concept demonstrating that this state-of-the-art technology can be used to effectively create mini guts with fibrosis in the lab has recently been published. Further information about this project can also be found in this press release.
This project was generously supported by Jonathan D. Rose, MD, PhD as part of the Jonathan D. Rose, MD, PhD, Pathology in Precision Medicine Research Collaborative.
