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BIOTEK2021-Bioteknologi for verdiskaping

A blood-based diagnostic test for coeliac disease

Alternative title: En blodbasert diagnostisk test for cøliaki

Awarded: NOK 4.8 mill.

Coeliac patients may present with diarrhea, abdominal pain or tiredness but the disease is caused by intolerance to dietary gluten proteins. The only treatment is a lifelong gluten-free diet, which in most cases will withdraw all symptoms. The disease is often detected after demonstration of antibodies directed against one of the body´s own proteins, so-called autoantibodies. However, a gastroduodenoscopy is still a diagnostic premise. This diagnostic approach implies medical personnel from different specialties, often hospitalization and a clear discomfort for the patient. Gluten-reactive CD4 T cells play a central role in the disease development. However, these cells have not previously been used for diagnosis as they are cumbersome to detect and very rare in peripheral blood. As the cells recognize pieces of gluten presented on so-called HLA-molecules, we have produced and linked HLA-molecules typically carried by coeliac patients to certain pieces of gluten (called tetramers). We have further used these tetramers to enrich and detect gluten-reactive CD4 T cells within blood samples from both patients and healthy individuals. In this project, we have increased test specificity and sensitivity by adding a further cell marker, decreased test volume to 48 ml of blood and including the HLA-types of other potential CD patients before providing an independent clinical validation of the diagnostic test. The clinical validation confirmed our preliminary results showing that we can detect a significant difference in the frequency of a further subclass of gluten-reactive CD4 T-cells between untreated and treated patients compared to healthy individuals. This method, simply based on a blood sample, seems to be equally sensitive and specific as the currently used diagnostic approach. More importantly, the clinical validation showed that the test is more sensitive in patients who are already on a gluten-free diet without any confirmed diagnosis. This is of great advantage, as currently available diagnostic tools have little to offer this growing group of patients. A company is interested in licensing our diagnostic test. This will hopefully make it available to the public in near future.

Coeliac disease (CD) is a chronic disorder of the small intestine provoked by the ingestion of gluten-proteins. The disease is strongly associated with certain HLA-variants, giving ground for a T-cell driven damage of intestinal epithelial cells in affect ed individuals. CD can be difficult to diagnose, and the majority of patients remain undiagnosed. Currently used methods for diagnosis of CD suffer from shortcoming related to poor sensitivity or invasiveness of the procedure. An increasing number of pat ients start on a gluten-free diet unprompted, complicating a subsequent diagnosing considerably. There is thus substantial unmet medical need for improved methods for diagnosing CD. We develop a new blood based diagnostic method, based on a highly sensit ive detection of gluten-reactive T cells binding HLA-tetramers representing immunodominant gluten epitopes. We observe a significant difference in the number of HLA-tetramer+ effector T-cells in untreated and treated patients compared to healthy controls. While preliminary data are very promising, further developments and more extensive clinical documentation are needed in order to reach a stage where industry is likely to license the diagnostic test under attractive terms. We will include all CD-related HLA-types (all potential CD patients), increase sensitivity by using the most dominant gluten T-cell epitopes, titrate blood volume, transfer the procedure to an automated platform and finally provide an independent clinical validation of the diagnostic test. As our putative diagnostic test is highly sensitive, non-invasive and can detect CD patients independently of the amount of gluten ingested, it should be highly competitive with currently used diagnostic procedures. The health economic benefits to society should also be substantial, as the test would not require specialized physicians and longer post intervention surveillance, as for the current invasive method.

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BIOTEK2021-Bioteknologi for verdiskaping