This article is more than 5 years old. Information may no longer be current.
Celiac symposium features latest in emerging therapeutics, gluten monitoring
Click Here to Manage Email Alerts
In this guest commentary, Jocelyn Silvester, MD, PhD, director of research for the Celiac Disease Program at Boston Children’s Hospital, recaps some of the most impactful research presented at the International Celiac Disease Symposium held last month in New Delhi, India.
The 17th International Celiac Disease Symposium in New Delhi focused attention on celiac disease in an area of high prevalence, yet relatively low awareness. Globally, the seroprevalence of celiac disease associated antibodies is 1.4% and the prevalence of celiac disease is estimated to be 0.7% (0.8% in Asia). The prevalence is higher in children, which suggests that the population prevalence of celiac disease will continue to increase.
A round table discussion of opportunities and challenges related to celiac disease in India highlighted the need for awareness, diagnosis and access to safe food — universal issues faced by the celiac disease community worldwide.
Several oral and poster presentations from Europe and North America highlighted the limitations in implementing a gluten-free diet even in settings where health care is relatively accessible and legislation regarding food labeling is in place.
One reason for relatively slow progress in developing alternative and adjunct therapies to a gluten-free diet is the absence of an animal model. In an award-winning presentation, Valerie Abadie, PhD, of the University of Montreal, Canada, presented a new mouse model that recapitulates many key aspects of celiac disease pathophysiology. The key breakthrough involved over-expressing IL-15 in an HLA-DQ8 expressing humanized mouse. IL-15 is a proinflammatory cytokine that stimulates proliferation of natural killer cells.
IL-15 also has an important role to promote survival of memory T cells in the absence of antigen exposure. Previous studies have shown that IL-15 is over-expressed in intestinal biopsies from patients with active celiac disease. In the mouse model, gluten exposure in the context of IL-15 overexpression in both the lamina propria and intestinal epithelial cells resulted in development of villous atrophy, intraepithelial lymphocytosis and generation of tissue transglutaminase antibodies. Importantly, villi recovered when gluten was withdrawn. The model was also dependent on coordinated response of B and T cells, which is a feature of celiac disease in humans.
At the conference, there were two preliminary reports regarding targeting of the IL-15 pathway for therapeutic purposes. Francisco León, MD, PhD, CEO and chief medical officer of Celimmune, presented unpublished results from two recently completed phase 2a trials of an anti-IL-15 monoclonal antibody (AMG 714) for the treatment of gluten-free diet non-responsive celiac disease (NRCD) and refractory celiac disease type II (RCD-II, a rare intestinal lymphoma that can complicate celiac disease).
In the study, AMG 714 appeared to provide effective therapeutic benefit for both patient populations across a range of endpoints. Notably, there was a favorable safety profile. This antibody had previously been investigated in rheumatoid arthritis and psoriasis by Amgen, but development for these indications has been discontinued despite efficacy in arthritis. According to León, plans for further development of AMG 714 for celiac disease and RCD-II are currently ongoing.
Results of a proof of concept study of BDZ-2, a novel dual IL-15/IL-21 inhibitory peptide, were presented by Paul Frohna, MD, PhD, of Bioniz Therapeutics. The study was conducted in collaboration with Bana Jabri, MD, PhD, at the University of Chicago. Intraepithelial lymphocytes were isolated from intestinal biopsy specimens from healthy persons and stimulated with IL-15 and IL-21 ex vivo. As expected, BDZ-2 attenuated downstream transcriptional changes induced by IL-15 and IL-21. The company hopes to begin clinical trials of BDZ-2 in 2018.
While exciting, these treatments must pass many hurdles before they may be available clinically. Thus, patients and their clinicians will still require better tools to follow and monitor a gluten-free diet for years to come. Angel Cebolla, PhD, of Biomedal SL presented comparative data of fecal and urine gluten immunogenic peptide testing in adults and children with celiac disease who were being seen for routine follow-up visits. This showed that traditional tools, including dietitian assessment and follow-up serologic tests, fail to identify many patients with gluten exposure.
Gliadin is minimally digested by enteral proteases; therefore, it is excreted in feces relatively intact and can be detected by antibodies to the ‘33mer’ — a 33 amino acid peptide sequence that contains overlapping epitopes that most patients with celiac disease recognize. These gluten immunogenic peptides are also present in urine.
A poster presented by Chaitan Khosla, PhD, of Stanford University provided insight into the identity of these urine gluten immunogenic peptides. Paired samples from a single subject with celiac disease were protein depleted then analyzed by using untargeted proteomics. There were 22 gluten specific peptides identified that were also present in 20 urine donors. These included known T cell epitopes as well as previously undefined gliadin peptides with no known physiological role.
Disclosures: Silvester reports no relevant financial disclosures.