Inflammatory bowel disease (IBD) has become a global disease with a worldwide prevalence of 0.3% and it is expected that there will be increasing number and incidence of IBD emerging in newly industrialized countries.1 Changing global burden of IBD may require further innovations in the delivery of care as the current practice only provides a mild relief from the symptoms.2 Recent research published in the Science Translational Medicine, has pioneered a new approach to relieve symptoms in IBD by targeted gene therapy.3
IBD is a chronic idiopathic disorder causing inflammation in the gastro-intestinal tract. People with IBD experience frequent episodes of abdominal pain, diarrhea and rectal bleeding in severe cases.2-4 The severity of the disease, prognosis and response to therapy depends on the complex interactions between genes and environmental factors. Suppressing inflammation is the main target of the standard-of-care and it is not effective enough to relieve symptoms among IBD patients.2,4 Therefore, genetic components associated with IBD should be considered as an important determinant in managing these patients.
Professor Thaddeus S. Stappenbeck at the Washington University School of Medicine, and colleagues found that patients with severe IBD expressed the SERPINE-1 gene and its associated protein PAI-1 (r2=0.72).3 Although the gene and the protein were previously identified in association with blood clotting, this is the first time it has been associated to inflammation.3 Identification and inhibiting the genes that lead to inflammation in IBD, could inhibit the inflammation at a higher level.3
Therefore, Professor Stappenbeck and his team have searched for genes that might contribute to IBD through pathways that are not directly related to inflammation.3 Concurrently, they have analyzed genetic data of 1,800 biopsy samples of people with IBD.3 These samples constituted of both inflamed and uninflamed gut tissues with the severities ranging from mild to severe.3
On explaining the genetic details, which they received from the sample population, Professor Stappenbeck commented “What’s most exciting here is that SERPINE-1 and its protein PAI-1 is expressed highly among people with the most severe disease and those who don’t respond to immunosuppression”.5
In order to simulate the clinical conditions, the research team developed a specific mouse model of IBD with same damage and symptoms in the gut as in an IBD patient.3 Compared to the mice in the control group, the IBD simulated mice lost weight and their gut tissue showed lesions and high levels of inflammatory proteins.3 Moreover, the expression of SERPINE-1 in the gut tissue of IBD simulated mice was significantly higher than in the control mice (p=0.0025).3 Professor Stappenbeck and colleagues then treated a group of IBD simulated mice with an experimental drug (MDI-2268), which blocks the action of the PAI-1. A parallel group of IBD simulated mice were treated with a placebo.3
When compared with the placebo, the IBD simulated mice treated with the experimental drug showed significant improvement in health. Their gut tissue lesions healed and reduced the signs of inflammation and subsequently the weight loss diminished. Furthermore, the expression of SERPINE-1 in the gut tissue of IBD simulated mice reduced significantly (p=0.0012).3 In the light of these findings, Professor Stappenbeck added, “We found a unique target that’s not an inflammatory molecule, yet blocking it reduces the inflammation and signs of disease, at least in mice”.5
The research team is hopeful that the findings will lead to next level of treatment for people with IBD, who finds less or no relief from the currently available treatments.3 “There’s a lot of interest in novel therapeutic approaches for IBD because inhibiting inflammatory molecules doesn’t work for all patients,” remarked Professor Stappenbeck.5
1. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2018;390(10114):2769-2778.
2. Damiao A, de Azevedo MFC, Carlos AS, et al. Conventional therapy for moderate to severe inflammatory bowel disease: A systematic literature review. World J Gastroenterol. 2019;25(9):1142-57.
3. Kaiko GE, Chen F, Lai CW, et al. PAI-1 augments mucosal damage in colitis. Sci Transl Med. 2019;11(482).
4. Magro F, Gionchetti P, Eliakim R, et al. Third European Evidence-based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 1: Definitions, Diagnosis, Extra-intestinal Manifestations, Pregnancy, Cancer Surveillance, Surgery, and Ileo-anal Pouch Disorders. J Crohns Colitis. 2017;11(6):649-70.
5. IBD: New approach to symptom relief looks promising, MedicalNewsToday. (Acceessed March 19, 2019 at :https://www.medicalnewstoday.com/articles/324685.php)