Submucosal injection of the RNA oligonucleotide GUT-1 in active ulcerative colitis patients: A randomized, double-blind, placebo-controlled phase 2a induction trial.
Journal
Journal of Crohn's & colitis
ISSN: 1876-4479
Titre abrégé: J Crohns Colitis
Pays: England
ID NLM: 101318676
Informations de publication
Date de publication:
30 Sep 2023
30 Sep 2023
Historique:
received:
19
05
2023
medline:
1
10
2023
pubmed:
1
10
2023
entrez:
30
9
2023
Statut:
aheadofprint
Résumé
Carbohydrate sulfotransferase 15 (CHST15) biosynthesizes sulfated matrix glycosaminoglycans and is implicated in intestinal inflammation and fibrosis. Here, we evaluate 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). In this randomized, double-blind, placebo-controlled, phase 2a study, we enrolled endoscopic active UC patients, refractory to conventional therapy, in 5 hospital centers 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. Twenty-eight patients were screened, 24 randomized and 21 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. Single dosing by submucosal injection of GUT-1 repressed CHST15 mucosal expression and may represent a novel induction therapy by modulating tissue remodeling in UC.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
Carbohydrate sulfotransferase 15 (CHST15) biosynthesizes sulfated matrix glycosaminoglycans and is implicated in intestinal inflammation and fibrosis. Here, we evaluate 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
METHODS
In this randomized, double-blind, placebo-controlled, phase 2a study, we enrolled endoscopic active UC patients, refractory to conventional therapy, in 5 hospital centers 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
RESULTS
Twenty-eight patients were screened, 24 randomized and 21 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
CONCLUSIONS
Single dosing by submucosal injection of GUT-1 repressed CHST15 mucosal expression and may represent a novel induction therapy by modulating tissue remodeling in UC.
Identifiants
pubmed: 37777210
pii: 7287358
doi: 10.1093/ecco-jcc/jjad162
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 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.