Submucosal Injection of the RNA Oligonucleotide GUT-1 in Active Ulcerative Colitis Patients: A Randomized, Double-Blind, Placebo-Controlled Phase 2a Induction Trial.

Autor:	Atreya R; Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany.; Deutsches Zentrum Immuntherapie, DZI, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Kühbacher T; Department of Internal Medicine/Gastroenterology, Asklepios Westklinikum, Hamburg, Germany., Waldner MJ; Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany.; Deutsches Zentrum Immuntherapie, DZI, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Hirschmann S; Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany.; Deutsches Zentrum Immuntherapie, DZI, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Drvarov O; Department of Internal Medicine/Gastroenterology, Asklepios Westklinikum, Hamburg, Germany., Abu Hashem R; Department of Internal Medicine/Gastroenterology, Asklepios Westklinikum, Hamburg, Germany., Maaser C; Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Lüneburg, Germany., Kucharzik T; Klinik für Allgemeine Innere Medizin und Gastroenterologie, Klinikum Lüneburg, Lüneburg, Germany., Dinter J; Klinik für Gastroenterologie und Hepatologie, Uniklinik Köln, Köln, Germany., Mertens J; Klinik für Gastroenterologie und Hepatologie, Uniklinik Köln, Köln, Germany., Schramm C; Klinik für Gastroenterologie und Hepatologie, Uniklinik Köln, Köln, Germany., Holler B; Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany., Mössner J; Klinik und Poliklinik für Gastroenterologie und Rheumatologie, Universitätsklinikum Leipzig, Leipzig, Germany., Suzuki K; Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata city, Niigata, Japan., Yokoyama J; Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata city, Niigata, Japan., Terai S; Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata city, Niigata, Japan., Uter W; Institut für Medizininformatik, Biometrie und Epidemiologie, University of Erlangen-Nürnberg, Erlangen, Germany., Yoneyama H; GUT Inc., Kochi-city, Kochi, Japan., Asakura H; Department of Gastroenterology, Niigata University Medical and Dental Hospital, Niigata city, Niigata, Japan., Hibi T; Center for Advanced IBD Research and Treatment, Kitasato Institute Hospital, Kitasato University, Minato-city, Tokyo, Japan., Neurath MF; Department of Medicine 1, University of Erlangen-Nürnberg, Erlangen, Germany.; Deutsches Zentrum Immuntherapie, DZI, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
Jazyk:	angličtina
Zdroj:	Journal of Crohn's & colitis [J Crohns Colitis] 2024 Mar 01; Vol. 18 (3), pp. 406-415.
DOI:	10.1093/ecco-jcc/jjad162
Abstrakt:	Background and Aims: Carbohydrate sulfotransferase 15 [CHST15] biosynthesizes sulphated matrix glycosaminoglycans and is implicated in intestinal inflammation and fibrosis. Here, we evaluate the efficacy and safety of the double-stranded RNA oligonucleotide GUT-1, a specific blocker of CHST15, as induction therapy in patients with ulcerative colitis [UC]. Methods: In this randomized, double-blind, placebo-controlled, phase 2a study, we enrolled endoscopically active UC patients, refractory to conventional therapy, in five hospital centres across Germany. Patients were randomized 1:1:1 using a block randomized technique to receive a single dosing of 25 nM GUT-1, 250 nM GUT-1, or placebo by endoscopic submucosal injections. The primary outcome measure was improvement of endoscopic lesions at weeks 2 or 4. The secondary outcome measures included clinical and histological responses. Safety was assessed in all patients who received treatment. Results: Twenty-eight patients were screened, 24 were randomized, and 21 were evaluated. Endoscopic improvement at weeks 2 or 4 was achieved by 71.4% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 28.6% in the placebo group. Clinical remission was shown by 57.1% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 14.3% in the placebo groups. Histological improvement was shown by 42.9% in the GUT-1 250 nM, 0% in the GUT-1 25 nM, and 0% in the placebo groups. GUT-1 250 nM reduced CHST15 expression significantly and suppressed mucosal inflammation and fibrosis. GUT-1 application was well tolerated. Conclusion: Single dosing by submucosal injection of GUT-1 repressed CHST15 mucosal expression and may represent a novel induction therapy by modulating tissue remodelling in UC. (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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