Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis

Jinxia Liu, MacNaughtan Jane, Annarein Kerbert, Theo Portlock, JM Gonzalez, Yi Jin, F Clasen, A Habtesion, H Ji, Q Jin, A Phillips, F Chiara, Ganesh Ingavle, C Jimenez, G Zaccherini, K Husi, M Gandia, P Cordero, J Soeda, L McConaghyJude Oben, Karen Church, Jia Li, Haifeng Wu, A Jalan, Peres Gines, Elsa Sola, Simon Eaton, Carrie Morgan, Michal Kowalski, Daniel Green, Lindsey Edwards, Jane Cox, Universidade de lisboa, Thomas Avery, Reiner Wiest, Francois Durand, Paolo Caraceni, Roberto Elosua, Joan Vila, Marco Pavesi, Vicente Arroyo, Nathan Davies, R Mookerjee, Victor Vargas, Susan Sandeman, Gautam Mehta, Saeed Shoaie, Julian Marchesi, Augustin Albillos, Fausto Andreola, Rajiv Jalan

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. Design: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. Results: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. Conclusions: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. Trial registration number: NCT03202498.
Original languageEnglish
Article number330699
Pages (from-to)1-16
Number of pages16
JournalGUT
DOIs
Publication statusPublished - 15 Apr 2024

Fingerprint

Dive into the research topics of 'Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis'. Together they form a unique fingerprint.

Cite this