Roadmap to the Cure of Early Childhood IBD
Infantile and very early onset (VEO) inflammatory bowel disease is a severe and debilitating form of intestinal inflammation that has shown the most dramatic increase in incidence over the past decade and now makes up over 25% of all Pediatric IBD. Infantile and VEO-IBD patients often suffer from a severe disease that does not respond to traditional therapies or surgery and unfortunately sometimes results in death. In order to understand and treat these young children we have established an international consortium made up of clinicians and scientists from North America, Europe, Australia, South America, Israel and the Middle East. Our singular mission is the ambitious goal of both understanding the basis for these diseases as well to develop effective therapies.
The Roadmap to the Cure of Early Childhood IBD project is led by co-PIs Scott Snapper from the United States, Aleixo Muise from Canada, and Christoph Klein from Germany (please see attached bios). All co-PIs have been committed to fully understanding the genetic and functional aspects of this form of IBD and their recent work has led to discovery of novel genes resulting in alternate therapies for defined subgroups of infantile and VEO-IBD. The collaboration brings together the InterNational Early Onset Pediatric IBD Cohort Study (NEOPICS) in North America and the Care for Rare Study in Europe. Furthermore, sites in Israel, Australia, Brazil, Chile, and the Middle East have joined our collaborative study. Together these consortia already have access to DNA from over 550 very early onset IBD patients many with stool, RNA, and biopsy samples. The inclusion of more US and European pediatric centers to the NEOPICS consortium will greatly increase the number of patient in a very short timeframe. This valuable resource will allow for rapid discovery of genetic determinants of infantile and VEO-IBD.
Pediatric Inflammatory Bowel Disease Biospecimen Repository
With the etiology of inflammatory bowel disease (IBD) still largely unknown, the pediatric inflammatory bowel disease biospecimen repository will create a resource for investigators to test research hypotheses in the areas of disease pathogenesis, diagnostics, and prognosis. Our repository will collect samples from patients with Crohn’s disease (CD) and ulcerative colitis (UC) as well as patients with debilitating, immune-mediated chronic bowel inflammation, including indeterminate colitis (IC) and primary immunodeficiencies that manifest with chronic bowel inflammation (eg. common variable immune deficiency, Wiskott-Aldrich syndrome). The development of an institutional IBD data registry will augment the value of the biospecimen repository as all samples will be annotated and linked to important clinical information. This will allow for easy integration of clinical and biological data.
GEM Project (A Multidisciplinary Human Study on the Genetic, Environmental and Microbial Interactions that Cause IBD)
The greatest identifiable risk for development of Crohn's disease is having a first-degree family member affected by Inflammatory Bowel Disease (IBD). The cause of IBD is unknown but speculated to involve complex gene-environment interactions where susceptible individuals mount abnormal host responses to environmental factors such as resident gut microorganisms. The GEM Project will attempt to determine if specific gene-environment triggers can be identified. For this prospective study, unaffected siblings of Crohn's disease patients will be recruited and information on environmental exposures will be collected prospectively while simultaneously obtaining and storing biological samples on all subjects with the cohort. These subjects will be followed for up to 6 years. When a "sufficient" number of subjects have developed Crohn's disease, a nested case-control sampling of this cohort will allow for a focused examination of the changes in the microbial flora, intestinal permeability, immune response to bacterial antigen (Ag) and immune regulation, in relation to expressed IBD susceptibility genes. This will allow us to determine which pathogenic events may have contributed to disease prior to disease development.
CCFA Microbiome Study
Complex interactions between host genetics, environment and immunity shape the intestinal microbiome. Abnormalities in any of these factors can provoke intestinal inflammation characteristic of IBD and many immunodeficiency syndromes. The precise nature of these interactions remains poorly understood. Genetic factors associated with Inflammatory Bowel Disease (IBD) explain a modest fraction of disease risk. While alterations of the intestinal microbiome have been described in IBD, no individual species or group of bacteria has been consistently associated with either Crohn’s disease (CD) or ulcerative colitis (UC). Likewise, it is not yet known what role microbial biomolecular activity may play in these diseases. Using novel computational approaches of 16S rDNA and whole genome sequencing, as well as meta- transcriptomics, metabolomics, and pathway analyses, we propose to define the relationship between host genetics and the intestinal microbiome. In particular, we have the capacity to study and identify functional elements of the microbiome that influence human subjects spanning the clinical spectrum from pre- symptomatic at risk individuals to those with established IBD as well as to those with immunodeficiences associated with intestinal inflammation. We have assembled a multidisciplinary team with recognized expertise and experience in these fields and will leverage existing resources to collect the necessary cohorts.
This multicenter open-label study is designed to evaluate the safety and efficacy of standardized initial therapy using either mesalamine, or corticosteroids then mesalamine for the treatment of children and adolescents newly diagnosed with ulcerative colitis.
The study will investigate the hypothesis that response to the initial 4 weeks of therapy as well as specific clinical, genetic, and immune parameters determined during the initial course of therapy will predict severe disease as reflected by need for escalation of medical therapy or surgery.
Oral Anti-CD3 for the Treatment of Active Ulcerative Colitis
Ulcerative colitis (UC) is a chronic disease of unknown etiology characterized by infiltration of inflammatory cells into the intestinal tract. Anti-CD3 monoclonal antibody (MAb) is an approved drug for intravenous use in the treatment of solid-organ transplantation and phase I/II trials have demonstrated possible efficacy for the treatment of UC. However, intravenous dosing has been limited by significant toxicities. Data from animal models suggest that anti-CD3 administered via the oral route is effective at treating a variety of autoimmune diseases. No side effects were observed in a recent phase I study of healthy subjects receiving oral anti-CD3 antibody.