Human Liver ORganoids as a Model to Study the Development of Non-Alcoholic SteatOhepatitis (NASH)

NCT06856252 | Recruiting

• 1 other identifier: REASON
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of the study is to generate and characterize three-dimensional models, called "assembloids", composed of the main liver cell populations (in particular from the co-culture of organoids with stellate cells, responsible for fibrogenesis, deriving from clinical samples). These models will be used in order to imitate the first phases of the onset of steatohepatitis, in conditions of altered lipid metabolism (induced through exposure to the main environmental determinants of this condition: excess fatty acids, fructose, cholesterol) in the presence or absence of the mutation I148M of PNPLA3. Other genetic variants will also be analyzed, such as TM6SF2, MBOAT7 and GCKR, which have previously been correlated with the development of non-alcoholic steatohepatitis. Further objectives will be: 1) identify new biomarkers of pathological activation of human stellate cells and progression of liver damage, to be subsequently validated in clinical case series for future use in clinical management for individual risk stratification; 2) study the epigenetic factors that underlie the onset of non-alcoholic steatohepatitis and its progression to fibrosis, cirrhosis and HCC; 3) evaluate the impact of antisense oligonucleotides directed against PNPLA3 on the severity of the "steatohepatitic" phenotype (lipid accumulation, lipotoxicity and inflammation and fibrogenesis) in assembloids

Conditions

NAFLD

Outcome Measures

Primary Outcomes (2)

• Generation of treatment-related assembloids

  Isolation of epithelial cells to impact assessment of the I148M variant on the steatohepatic phenotype in human liver assembloids and analysis of the variants of the TM6SF2, MBOAT7 and GCKR genes previously related to the development of non-alcoholic steatohepatitis

  up to 35 months

• Rate of PNPLA3 p.I148M variant in steatohepatitis development through human liver organoids

  * Knowledge of the gene expression of lipotoxicity and expression of inflammatory markers; * Knowledge of the molecular mechanisms to evaluate the state of activation of star cells, the metabolism of retinol and the deposition of extracellular matrix and estimate

  up to 35 months

Study Arms (1)

Liver resection to isolate cells

EXPERIMENTAL

Isolation and culture of organoids Isolation of hepatic stellate cells Isolation and culture of sinusoidal stellate cells Generation of assembloids

Genetic: Liver resection to isolate cells

Interventions

Liver resection to isolate cells GENETIC

Isolation and culture of organoids Isolation of hepatic stellate cells Isolation and culture of sinusoidal stellate cells Generation of assembloids

Liver resection to isolate cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

Adult patients who have given consent to participate in the study and listed for the following procedures will be included: * liver biopsy for suspected non-alcoholic steatohepatitis (NASH) at the time of diagnosis; * liver resection for hepatocarcinoma or other liver lesions (including secondaries from other neoplasms and benign focal lesions, which will allow obtaining healthy starting liver tissue); * post-transplant healthy liver biopsies; * cholecystectomies. It will also be required: * availability to sign informed consent for the study * availability of DNA sample for genetic analysis and clinical data, * blood sampling for genetic and epigenetic analyzes and analysis of non-coding RNAs (lncRNAs, miRNAs and circRNAs). Patients will be excluded who present: * positivity for chronic viral hepatitis (HCV-RNA and/or HBsAg); * positivity to other liver diseases such as autoimmune and viral hepatitis (hepatitis B and C), hereditary hemochromatosis, alpha-1-antitrypsin deficiency, Wilson's disease.

Contact the study team to discuss eligibility requirements. They can help determine if this study is right for you.

Sponsors & Collaborators

• Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico: lead

Study Sites (1)

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica

Milan, Milano, 20122, Italy

RECRUITING

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

Central Study Contacts

Luca Vittorio Carlo Valenti

CONTACT

02 5503 6595; luca.valenti@policlinico.mi.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: Biospecimen collection of tissue samples from patients undergoing liver resection (both intratumoral and extratumoral tissues in case of hepatocellular carcinoma) or collected from post-transplant whole livers. These samples will allow us to isolate cells (ovalocytes - hepatic progenitor cells) to generate organoids from normal liver tissues (cholecystectomy) and suspected NASH.

Study Record Dates

• First Submitted: March 8, 2024
• First Posted: March 4, 2025
• Study Start: July 1, 2021
• Primary Completion (Estimated): July 31, 2030
• Study Completion (Estimated): July 31, 2032
• Last Updated: November 20, 2025

Record last verified: 2025-11

Locations

IT (1)