Crohn's disease Archives - Sanford Burnham Prebys

Tag: Crohn’s disease

Institute News

Discovery from the lab of Carl Ware, PhD leads to clinical trial in pediatric Crohn’s disease

AuthorJessica Moore
Date

December 8, 2016

child with abdominal pain

Just about any of the 700,000-plus people in the U.S. who have Crohn’s disease, a chronic condition in which portions of the intestine are inflamed, can tell you that better treatments are urgently needed. Even with medication, most experience flare-ups that keep them away from work or school for days or weeks at a time with diarrhea and severe abdominal pain.

A soon-to-commence clinical trial could offer Crohn’s patients new hope. The trial will test a drug made possible by a discovery from the lab of Carl Ware, PhD, professor and director of the Infectious and Inflammatory Diseases Center at Sanford Burnham Prebys Medical Discovery Institute (SBP). Almost two decades ago, his team identified an immune-regulating protein called LIGHT, and went on to show that it promotes intestinal inflammation. The new drug is a protein that prevents LIGHT from binding its target receptor on T cells, the immune cells that drive inflammation in Crohn’s disease.

“We’re thrilled to see our research through to a clinical trial,” said Ware. “We’ve focused on patients with a rare mutation that causes especially severe, early-onset disease. If the drug proves beneficial to those patients, we expect to pursue a larger trial in patients with typical Crohn’s.”

The trial will test the LIGHT-blocking drug in children with Crohn’s disease who carry a mutation in the gene for a protein called DcR3, which normally limits the amount of LIGHT and two other related pro-inflammatory molecules. The genomics company Medgenics will conduct the clinical trial with physician-scientist Robert Baldassano, MD, at the Children’s Hospital of Philadelphia.

Ware’s lab will be involved in fundamental research aspects of the study, developing assays to measure levels of LIGHT in patient plasma. In parallel, his team will be studying how the drug affects the microbiome in animal models.

“We are also applying what we’ve learned about LIGHT and the receptors it interacts with to other autoimmune diseases,” said John Sedy, PhD, research assistant professor in Ware’s group. “We’re working towards treatments that modulate the immune system in different ways.” 

Institute News

New therapeutic target for Crohn’s disease

AuthorJessica Moore
Date

September 20, 2016

cell image

Research from the Sanford Burnham Prebys Medical Discovery Institute (SBP) identifies a promising new target for future drugs to treat inflammatory bowel disease (IBD). The study, published in Cell Reports, also indicates that another protein, protein kinase C (PKC) λ/ι, may serve as a biomarker of IBD severity.

“The intestine is protected by specialized cells, called Paneth cells, that secrete antimicrobial peptides,” said Jorge Moscat, PhD, deputy director and professor in the NCI-designated Cancer Center and senior author of the paper. “We found that maintaining normal numbers of Paneth cells requires PKC λ/ι, and that the amount of PKC λ/ι decreases as IBD gets worse. We also discovered a way to prevent Paneth cell loss—inhibiting a protein called EZH2, which could be a new therapeutic strategy for IBD.”

IBD, which includes Crohn’s disease and ulcerative colitis, affects 1.4 million people in the U.S. These chronic conditions are often debilitating, as they cause unpredictable abdominal pain and diarrhea. Because current medications only help control symptoms and not the underlying disease, 70% of Crohn’s patients and 30% of those with colitis must eventually undergo surgery. In addition, IBD increases risk of intestinal cancer by as much as 60%.

“We also examined the effect of PKC λ/ι on tumor formation,” said Maria Diaz-Meco, PhD, also a professor in the Cancer Center and co-author of the paper. “In contrast to some previous studies indicating that it might promote cancer development, we demonstrate that in the intestine, PKC λ/ι is protective.”

“We inactivated the PKC λ/ι gene in the intestine of mice, which caused them to have very few Paneth cells,” added Diaz-Meco. “Without Paneth cells, the intestine is more susceptible to bacterial infiltration, which leads to inflammation. Since inflammation favors cancer, it makes sense that PKC λ/ι is a tumor suppressor in this setting.”

To find a way to boost Paneth cell numbers and possibly treat IBD, the team looked for what drives the deficit in these protector cells. The key link was overactive EZH2, which turns off genes needed to generate Paneth cells.

“We used an in vitro model—‘mini guts’ in a dish—to show that blocking EZH2 helps return the number of Paneth cells to normal,” said Yuki Nakanishi, MD, a postdoctoral fellow in the Moscat/ Diaz-Meco lab and lead author of the work. “This demonstrates that inhibiting EZH2 could be a new way to slow the progression of IBD.”

Importantly, the team verified the relevance of their findings in intestinal biopsy samples from 30 patients with Crohn’s disease. Disease progression correlated with lower levels of PKC λ/ι.

“EZH2 inhibitors are currently being developed by the pharmaceutical industry to treat other cancers, so they could be tested for IBD relatively soon,” said Moscat. “But first, we need to do preclinical studies to test whether they block progression of the disease.”

The paper is available online here.

Institute News

Research points to new ways to treat inflammatory bowel diseases

Authorjmoore
Date

March 16, 2016

Header image

A new paper in Nature co-authored by SBP’s Randal Kaufman, PhD, reveals how briefly reducing dietary amino acids could help patients with inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. The research shows for the first time that a specific amino acid sensor controls gut inflammation.

These results, generated in the laboratory of Bali Pulendran, PhD, of Emory University, could also lead to new drugs for IBD, which are sorely needed—currently available drugs don’t work for many patients.

What was known before this study

The amino acid sensor studied, GCN2, is one of four sensors that activate the integrated stress response (ISR) (the other sensors respond to different types of cellular stress). Activation of the ISR alters gene expression in ways that help cells survive: facilitating efficient utilization of nutrients, combating oxidative stress, and repairing DNA damage. While previous research had shown that the ISR helps limit gut inflammation, this is the first to implicate GCN2.

Significance

The findings “highlight the capacity of the immune system to sense and adapt to environmental changes, such as nutritional starvation, that cause cellular stress,” said Kaufman.

“This response may have evolved as a negative feedback mechanism to limit inflammation. This mechanism ensures that sufficient building blocks are available for the tissue regeneration required to repair the damage caused by inflammation and prevents the immune response from getting out of control.”

Implications for IBD

While GCN2’s anti-inflammatory activity can be triggered by a low-amino acid diet, reducing protein intake is not a feasible long-term treatment for IBD because it would generally impair the immune system. If human studies confirm that GCN2 is also protective in human disease, drugs that target GCN2 or later steps in the ISR could be developed to treat IBD.

Next steps

“We plan to investigate whether this pathway is involved in regulating other types of inflammation. If it is, this discovery could be important for treating other diseases like rheumatoid arthritis or multiple sclerosis,” Kaufman added.

The paper is available online here.