Oral/Topical D-Peptide TNF Inhibitors for Inflammatory Bowel Disease
Abstract
Topic Area: Inflammatory Bowel Disease Inflammatory bowel disease (IBD) is a serious condition in which the intestinal lining is chronically inflamed. Symptoms include chronic diarrhea, ulceration, bleeding, and ultimately colorectal cancer. An estimated 1.6 million Americans have IBD. The cause of IBD is not yet fully understood, but a master protein regulator of inflammation called tumor necrosis factor (TNF) is elevated in IBD patients. The most effective current treatments for moderate to severe IBD are a group of injectable drugs that block TNF. These drugs are effective, but have numerous drawbacks that limit their utility including their very high cost (>$15,000/year), requirement for injection, specialized storage requirements (suboptimal for use in the field), side effects (most prominently increasing susceptibility to infection), and reduced effectiveness when patients develop antibodies against them. In this project, we propose to develop a novel class of TNF inhibitors that would overcome these limitations and enable more widespread use for IBD treatment. Specifically, we will develop D-peptide inhibitors of TNF. D-peptides are the mirror-images of naturally occurring peptides (called L-peptides). These non-natural peptides resist degradation in the body and are poorly recognized by the immune system. As a result, D-peptides are much longer lived in the body and can be given less frequently at much lower doses. As a synthetic product, they are much cheaper to produce than existing anti-TNF drugs (which are grown in cells). We propose to discover highly potent and specific anti-TNF D-peptides using a special screening technique (mirror-image phage display) that can simultaneously evaluate billions of peptides to identify those that block TNF most effectively. Since D-peptides are not digested in or absorbed from the gastrointestinal tract, they provide an ideal way to directly deliver a TNF inhibitor to the gut lining when taken by mouth. The advantage of such an approach is that TNF function would only be inhibited at the sites of disease (in the gut lining), while sparing TNF function in the rest of the body (allowing normal immune system function, unlike with current TNF inhibitors that distribute throughout the body and globally suppress the immune system). In this grant, we propose to discover, characterize, and optimize D-peptides that will inhibit TNF with high potency. This lead inhibitor would provide a strong foundation for the next step in drug development, including proof-of-concept efficacy studies in animal models of IBD and comprehensive safety studies in animals prior to starting clinical trials in humans. In addition to providing a valuable and more cost-effective option for IBD treatment, this work will open the door to other localized applications for TNF inhibition (e.g., for acute inflammation syndromes in the lung or brain). More generally, the D-peptide discovery technologies developed and validated here will also facilitate future D-peptide therapeutic applications against diverse disease targets.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610350
Entities
People
- Michael S Kay
Organizations
- United States Army
- University of Utah