BARCELONA—Acute-on-chronic liver failure is a syndrome associated with high short-term mortality and characterized by multiple organ failures and excessive systemic inflammation that occurs in one third of the patients hospitalized for acute decompensation of cirrhosis. A new study shows that when used in combination, granulocyte-colony stimulating factor (G-CSF) and TAK-242, an inhibitor of Toll-like receptor-4 (TLR-4), inhibit inflammation and promote hepatocyte regeneration in two mouse models of ACLF. The study published on 1 November 2022 in Journal of Hepatology, provides evidence of the effectiveness of this drug combination and its potential to be repurposed for the treatment of ACLF.
In patients with ACLF, damage-associated molecular patterns (DAMPs) are released from the injured tissues and pathogen-associated molecular patterns (PAMPs) are increased as a result of infections and/or gut bacterial translocation. Both DAMPs and PAMPs activate Toll-like receptors which in turn induce an inflammatory response. Moreover, while hepatocyte proliferation is a positive predictor of survival, liver regeneration is impaired in ACLF. Administration of G-CSF has been proven to accelerate liver regeneration and improve survival in mice, yet in patients with decompensated cirrhosis, alcoholic hepatitis and ACLF these results have failed to be reproduced.
“At the time when we designed the GRAFT study where we tested G-CSF as single therapy for ACLF in men, our assumption that this therapy improves survival was based on several smaller single center trials, but we underestimated the importance and significance of inflammation in the complex network of pathomechanisms. Consequently, the GRAFT study showed that G-CSF is not effective in ACLF and in animal models G-CSF lead to excess mortality”, said Cornelius Engelmann, Principal Investigator at Charité – Universitätsmedizin Berlin, and first author in the paper.
Under the hypothesis that G-CSF may worsen systemic inflammation via stimulation of the bone marrow to produce neutrophils and release them into the bloodstream, researchers at Charité – Universitätsmedizin Berlin, Germany, Sapienza University of Rome, Italy, University of Edinburgh, UK, Leipzig University Medical Center, Germany, University College London, UK and EF CLIF, Spain, aimed to test whether addition of TAK-242 could alleviate G-CSF-related liver injury while preserving its ability to induce hepatocyte proliferation.
In chronic liver disease, hepatocellular senescence inhibits proliferation of damaged hepatocytes and ensures cell cycle arrest preventing tissue repair and regeneration. Using an ACLF mouse model, where liver fibrosis was chemically induced and lipopolysaccharide (LPS) was injected to induce ACLF, the authors found that administration of TAK-242 abrogated the inflammatory response triggered by G-CSF treatment while able to restore the proliferative capacity of hepatocytes. Using a second mouse model, where galactosamine instead of LPS was used after chemical induction of liver fibrosis, researchers aimed to study the beneficial effect of the G-CSF and TAK-242 combined treatment on liver injury and regeneration under moderate inflammatory conditions. Indeed, galactosamine-induced liver damage was reversed by G-CSF and TAK-242 alone, but response to treatment was superior when these drugs were used in combination. The combination of G-CSF and TAK-242 also resulted in a reduction of senescence markers and increase of hepatocyte proliferation, thus suggesting that the regenerative potential of G-CSF is dependent on the severity of liver injury and systemic inflammation.
“These results allow us for the first time to test a combinatorial therapy to treat patients with ACLF. This treatment maximizes the beneficial effects of each individual component while minimizing their side effects. Reducing inflammation and fostering regeneration may be of great relevance especially for those patients where liver transplantation is not a treatment option”, concluded Engelmann.
“The A-TANGO Consortium that is funded by a grant from the European Commission will perform a randomized, placebo-controlled clinical trial comparing the clinical effect of the combination of G-CSF and TAK-242 versus TAK-242 alone versus placebo in patients with ACLF” explained Rajiv Jalan, Principal Investigator at University College London and at EF CLIF, and senior author in the paper. "The results will provide a potential new therapy for patients with ACLF", he added.
This study received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 945096.
Other authors on the study are Abeba Habtesion, Mohsin Hassan, Annarein J.C. Kerbert, Linda Hammerich, Simone Novelli, Marco Fideleo, Alexandra Philips, Nathan Davies, Sofia Ferreira-Gonzalez, Stuart J. Forbes, Thomas Berg, and Fausto Andreola.
Engelmann, C., Habtesion, A.; Hassan, M., Kerbert, A.J.C.; Hammerich, L.; Novelli, S.; Fideleo, M.; Philips, A.; Davies, N.; Ferreira-Gonzalez, S.; Forbes, S.J.; Berg, T.; Andreola, F.; Jalan, R. Combination of G-CSF and a TLR4 inhibitor reduce inflammation and promote regeneration in a mouse model of ACLF. J. Hepatol. 2022 77: P1325–1338. DOI: 10.1016/j.jhep.2022.07.006
The EU-funded A-TANGO project aims to bring a novel treatment (G-TAK) that combines a drug known to targets inflammation (TAK-242) and granulocyte colony-stimulating factor (G-CSF) which improves hepatocyte proliferation. Alongside the identification of novel biomarkers for patient selection and prognosis, G-TAK is expected to improve the clinical outcome of patients with alcoholic liver disease who are at high risk to develop acute-on-chronic liver failure (ACLF). The A-TANGO Consortium will perform a phase IIb randomized controlled trial to evaluate the safety and effectiveness of this novel treatment.
About EF CLIF
The European Foundation for the Study of Chronic Liver Failure (EF CLIF) is a private non-profit organization connecting biomedical researchers and healthcare professionals with each other, with patients and patient associations, and with society. The fundamental purpose of EF CLIF, reflected in its founding Statements of 2015, is to advance knowledge and promote research and education in liver disease to improve the prognosis of patients living with chronic liver failure.
The Foundation has made pioneering efforts in conducting a series of large, international prospective studies that have been instrumental in reclassifying the trajectory of patients with chronic liver failure and led to the clinical, prognostic and pathophysiological definition of the syndrome referred to as “acute-on-chronic liver failure” characterized by acute decompensation of cirrhosis, severe systemic inflammation, organ failures, and high short-term mortality. We are inspiring best clinical practices for the management of patients with chronic liver failure and promoting a more sustainable and equitable healthcare system.
Within the Foundation, the European Association for the Study of the Liver (EASL) Chair supports research activities through the EASL-CLIF Consortium, a network of 117 tertiary care and university hospitals in 28 European countries. The Grifols Chair promotes translational studies in centers across Europe and North America within the framework of the European Network for Translational Research (ENTR) with 25 centers in 8 countries. Over the last five years, the Foundation has successfully expanded its geographical scope providing the context to support transcontinental collaborative research projects. The Global Projects chapter provides the framework to promote research in cirrhosis across the world with the aim to help to build consensus and ensure health equity worldwide.