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Objectives: Glucagon-like peptide 2 (GLP2) is an intestinal growth factor that has been shown to stimulate intestinal growth and reduce disease severity in preclinical models of short bowel syndrome and inflammatory bowel disease. Teduglutide, a recombinant human GLP2 variant (GLP2-2G), has increased half-life and stability as compared to the native GLP2 peptide, but still requires twice daily dosing in preclinical models and daily dosing in the clinic. The goal of this study was to produce and characterize the preclinical pharmacokinetic and therapeutic properties of GLP2-2G-XTEN, a novel, long-acting form of GLP2-2G.
Methodology And Results: A GLP2-2G-XTEN fusion protein with extended exposure profile was produced by genetic fusion of GLP2-2G peptide to XTEN, a long, unstructured, non-repetitive, hydrophilic sequence of amino acids. The serum half-life of GLP2-2G-XTEN in mice, rats and monkeys was 34, 38 and 120 hours, respectively. Intestinotrophic effects were demonstrated in normal rats, where GLP2-2G-XTEN administration resulted in a significant increase in both small intestine weight and length. Efficacy of the GLP2-2G-XTEN protein was compared to that of GLP2-2G peptide in a rat Crohn's disease model, indomethacin-induced inflammation. Prophylactic administration of GLP2-2G-XTEN significantly increased the length, reduced the number of trans-ulcerations and adhesions, and reduced the TNFα content of the small intestine. GLP2-2G-XTEN demonstrated greater in vivo potency as compared to GLP2-2G peptide, and improvement in histopathology supported the GLP2-2G-XTEN treatment effects.
Conclusions And Significance: GLP2-2G-XTEN is intestinotrophic and demonstrates efficacy in a rat Crohn's disease model requiring a lower molar dose and less frequent dosing relative to GLP2-2G peptide. Allometric scaling based on pharmacokinetics from mouse, rat and monkey projects a human half-life of 240 hours. These improvements in preclinical pharmacokinetics and dosing indicate that GLP2-2G-XTEN may offer a superior therapeutic benefit for treatment of gastrointestinal diseases including Crohn's disease.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506575 | PMC |
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050630 | PLOS |
Am J Case Rep
December 2024
Department of Infectious Diseases, Hôpitaux Civils de Colmar, Colmar, France.
BACKGROUND Hepatic lesion in a young woman can lead to multiple diagnostic hypotheses, mainly infection and tumor. Crohn's disease (CD) is hardly evoked by clinicians but is reportedly associated with liver damage, especially diffuse granulomas and aseptic abscess. IgA deficiency has been associated with celiac disease or inflammatory bowel disease, including CD.
View Article and Find Full Text PDFJ Pediatr Gastroenterol Nutr
December 2024
Division of Pediatric Gastroenterology, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina, USA.
Objectives: Intestinal ultrasound (IU) has emerged as an alternative to detect bowel wall inflammation. The aim of this study was to compare IU findings to clinical disease, fecal calprotectin (FC), and endoscopic findings in newly diagnosed pediatric inflammatory bowel disease (IBD) patients.
Methods: This study was a 1-year, single-center, prospective study.
Therap Adv Gastroenterol
December 2024
Department of Gastroenterology, The First Affiliated Hospital of Sun Yat-sen University, No. 58 Zhongshan Road 2, Guangzhou 510080, China.
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Curr Res Microb Sci
November 2024
Applied Microbiology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
The global COVID-19 pandemic, which began in 2019, is still ongoing. SARS-CoV-2, also known as the severe acute respiratory syndrome coronavirus 2, is the causative agent. Diarrhea, nausea, and vomiting are common GI symptoms observed in a significant number of COVID-19 patients.
View Article and Find Full Text PDFFood Funct
December 2024
College of Biosystems Engineering and Food Science, National-Local Joint Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, Integrated Research Base of Southern Fruit and Vegetable Preservation Technology, Zhejiang International Scientific and Technological Cooperation Base of Health Food Manufacturing and Quality Control, Zhejiang University, Hangzhou 310058, China.
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), are chronic conditions characterized by periods of intestinal inflammation and have become global diseases. Dietary pectins have shown protective effects on IBD models. However, the development of pectin-based diet intervention for IBD individuals requires knowledge of both the bioactive structural patterns and the mechanisms underlying diet-microbiota-host interactions.
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