EP-4740018-A1 - LARGE EXTRACELLULAR VESICLES AS BIOMARKERS FOR PREDICTING ORGAN FAILURES AND SURVIVAL TIME OF PATIENTS SUFFERING FROM AN ACUTE DECOMPENSATION OF CIRRHOSIS

Abstract

Acute decompensation (AD) of cirrhosis is defined by the acute development of ascites, gastrointestinal haemorrhage, hepatic encephalopathy or infection. The PREDICT study distinguishes three different phenotypic sub-types in patients with AD but without ACLF according to hospital readmission and development of ACLF: stable decompensated cirrhosis, unstable decompensated cirrhosis and pre-ACLF group. Predicting the phenotypes in patients with AD would thus be useful, since mortality rates vary considerably between the three phenotypes. This will allow us a better management of patients with AD. Now the inventors used proteomics analysis of proteins carried by plasma lEVs to identify novel EV protein biomarkers having higher concentrations in the plasma of patients who will develop organ failure than in those who will not (Tenascin C and 0LFM4 lEVs). Moreover, the inventors identified 2 plasma lEVs (FCGBP and Tenascin C) predicting survival in PREDICT. Tenascin C was the most robust one since also predicting survival in ACLARA. Accordingly, the present invention relates to large extracellular vesicles as biomarkers for predicting organ failures and survival time of patients suffering from an acute decompensation of cirrhosis.

Inventors

• RAUTOU, Pierre-Emmanuel

Assignees

• Institut National de la Santé et de la Recherche Médicale
• Assistance Publique-Hôpitaux de Paris (APHP)
• Université Paris Cité

Dates

Publication Date

20260513

Application Date

20240702

Claims (1)

1. CLAIMS: 1. A method of predicting whether a patient suffering from an acute decompensation of cirrhosis is at risk of developing an organ failure comprising determining the level of Tenascin C large extracellular vesicles (lEV)s in a blood sample obtained from the patient wherein said level indicates the risk that the patient will have an organ failure. 2. A method of predicting whether a patient suffering from an acute decompensation of cirrhosis is at risk of developing an organ failure comprising determining the level of OLFM4 large extracellular vesicles (lEV)s in a blood sample obtained from the patient wherein said level indicates the risk that the patient will have an organ failure. 3. A method of predicting the survival time of a patient suffering from an acute decompensation of cirrhosis comprising determining the level of Tenascin C large extracellular vesicles (lEV)s in a blood sample obtained from the patient wherein said level correlates with the survival time of the patient. 4. A method of predicting the survival time of a patient suffering from an acute decompensation of cirrhosis comprising determining the level of FCGBP large extracellular vesicles (lEV)s in a blood sample obtained from the patient wherein said level correlates with the survival time of the patient.

Description

LARGE EXTRACELLULAR VESICLES AS BIOMARKERS FOR PREDICTING ORGAN FAILURES AND SURVIVAL TIME OF PATIENTS SUFFERING FROM AN ACUTE DECOMPENSATION OF CIRRHOSIS FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular hepatology. BACKGROUND OF THE INVENTION: Acute decompensation (AD) of cirrhosis is defined by the acute development of ascites, gastrointestinal haemorrhage, hepatic encephalopathy or infection. The PREDICT study distinguishes three different phenotypic sub-types in patients with AD but without ACLF according to hospital readmission and development of ACLF: stable decompensated cirrhosis, unstable decompensated cirrhosis and pre-ACLF group (Trebicka J, Fernandez J, Papp M, Caraceni P, Laleman W, Gambino C, Giovo I, Uschner FE, Jimenez C, Mookerjee R, Gustot T, Albillos A, Bañares R, Janicko M, Steib C, Reiberger T, Acevedo J, Gatti P, Bernal W, Zeuzem S, Zipprich A, Piano S, Berg T, Bruns T, Bendtsen F, Coenraad M, Merli M, Stauber R, Zoller H, Ramos JP, Solè C, Soriano G, de Gottardi A, Gronbaek H, Saliba F, Trautwein C, Özdogan OC, Francque S, Ryder S, Nahon P, Romero-Gomez M, Van Vlierberghe H, Francoz C, Manns M, Garcia E, Tufoni M, Amoros A, Pavesi M, Sanchez C, Curto A, Pitarch C, Putignano A, Moreno E, Shawcross D, Aguilar F, Clària J, Ponzo P, Jansen C, Vitalis Z, Zaccherini G, Balogh B, Vargas V, Montagnese S, Alessandria C, Bernardi M, Ginès P, Jalan R, Moreau R, Angeli P, Arroyo V; PREDICT STUDY group of the EASL-CLIF Consortium. The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology. J Hepatol. 2020 Oct;73(4):842-854. doi: 10.1016/j.jhep.2020.06.013. Epub 2020 Jul 13. PMID: 32673741.). Predicting the phenotypes in patients with AD would thus be useful, since mortality rates vary considerably between the three phenotypes. This will allow us a better management of patients with AD. SUMMARY OF THE INVENTION: The present invention is defined by the claim. In particular, the present invention relates to large extracellular vesicles as biomarkers for predicting organ failures and survival time of patients suffering from an acute decompensation of cirrhosis. DETAILED DESCRIPTION OF THE INVENTION: Main definitions: As used herein, the term "cirrhosis" refers to a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated), leading to loss of liver function. As used herein, the term “acute decompensation of cirrhosis” has its general meaning in the art and defines the acute development of clinically evident ascites, hepatic encephalopathy, gastrointestinal haemorrhage or any combination of these in patients with or without prior history of these complications. As used herein, the term the “Child–Pugh score” has its general meaning in the art and refers to the score used to assess the prognosis of chronic liver disease, mainly cirrhosis as described by Child CG, Turcotte JG (1964). "Surgery and portal hypertension". In Child CG (ed.). The liver and portal hypertension. Philadelphia: Saunders. pp. 50–64. Although it was originally used to predict mortality during surgery, it is now used to determine the prognosis, as well as the required strength of treatment and the necessity of liver transplantation. The score employs five clinical measures of liver disease including total bilirubin, serum albumin, prothrombin time prolongation (or INR), ascites and hepatic encephalopathy. Each measure is scored 1–3, with 3 indicating most severe derangement. Chronic liver disease is classified into Child–Pugh class A to C, as depicted in Table A. Points Class One-year survival Two-year survival 5–6 A 100% 85% 7–9 B 80% 60% 10–15 C 45% 35% Table A: Child–Pugh score and significance. As used herein, the term “organ failure” has its general meaning in the art and refers to a condition where an organ does not perform its expected function. Organ failure relates to organ dysfunction to such a degree that normal homeostasis cannot be maintained without external clinical intervention. Examples of organ failure include without limitation renal failure, liver failure, heart failure, and respiratory failure. Typically, organ failure is assessed by the Sequential Organ Failure Assessment (SOFA) score that is a simple and objective score that allows for calculation of both the number and the severity of organ dysfunction in six organ systems (respiratory, coagulatory, liver, cardiovascular, renal, and neurologic). As used herein, the term "multiple organ failure" or "MOF" denotes a clinical situation wherein an organ failure occurs in 2 or more organs. As used herein, the term “acute-on-chronic liver failure” or “ACLF” refers to the development of a syndrome associated with a high risk of short-term death (i.e., death <28 days after hospital admission) in patients with acu