TY - JOUR
T1 - Clinical, experimental and pathophysiological effects of Yaq-001
T2 - a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis
AU - Liu, Jinxia
AU - MacNaughtan, Jane
AU - Kerbert, Annarein J C
AU - Portlock, Theo
AU - Martínez Gonzalez, Javier
AU - Jin, Yi
AU - Clasen, Frederick
AU - Habtesion, Abeba
AU - Ji, Huoyan
AU - Jin, Qin
AU - Phillips, Alexandra
AU - De Chiara, Francesco
AU - Ingavle, Ganesh
AU - Jimenez, Cesar
AU - Zaccherini, Giacomo
AU - Husi, Katherine
AU - Rodriguez Gandia, Miguel Angel
AU - Cordero, Paul
AU - Soeda, Junpei
AU - McConaghy, Lynda
AU - Oben, Jude
AU - Church, Karen
AU - Li, Jia V
AU - Wu, Haifeng
AU - Jalan, Aarti
AU - Gines, Pere
AU - Solà, Elsa
AU - Eaton, Simon
AU - Morgan, Carrie
AU - Kowalski, Michal
AU - Green, Daniel
AU - Gander, Amir
AU - Edwards, Lindsey A
AU - Cox, I Jane
AU - Cortez-Pinto, Helena
AU - Avery, Thomas
AU - Wiest, Reiner
AU - Durand, Francois
AU - Caraceni, Paolo
AU - Elosua, Roberto
AU - Vila, Joan
AU - Pavesi, Marco
AU - Arroyo, Vicente
AU - Davies, Nathan
AU - Mookerjee, Rajeshwar P
AU - Vargas, Victor
AU - Sandeman, Susan
AU - Mehta, Gautam
AU - Shoaie, Saeed
AU - Marchesi, Julian
AU - Albillos, Agustín
AU - Andreola, Fausto
AU - Jalan, Rajiv
N1 - Funding Information:
This study was performed with support from a grant from the EU H2020, Grant Agreement number: 634579\u2014CARBALIVE\u2014H2020-PHC-2014-2015/H2020-PHC-2014 programme. JMarchesi and the Division of Digestive Diseases at Imperial College London receives financial support from the NIHR Imperial Biomedical Research Centre.
Funding Information:
We would like to thank Fraser Simpson (Department of Genetics, Evolution and Environment, University College London) for his support to perform the Nanostring. The urinary NMR studies were facilitated by a Medical Research Council research grant under the High-throughput 'omic' Science and Imaging funding scheme (MC_PC_13045). University of Brighton coauthors acknowledge Prof Sergey Mikhalovsky and Dr Carol Howell in discussion and research leading to the CARBALIVE grant. The authors would like to thank all the patients and public who provided input into designing the study and those that took part in the study.
Publisher Copyright:
© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.
PY - 2024/6/6
Y1 - 2024/6/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85191370362&partnerID=8YFLogxK
U2 - 10.1136/gutjnl-2023-330699
DO - 10.1136/gutjnl-2023-330699
M3 - Article
C2 - 38621924
SN - 0017-5749
VL - 73
SP - 1183
EP - 1198
JO - Gut
JF - Gut
IS - 7
M1 - 330699
ER -