NAFLDREASONNCT06856252
Human Liver ORganoids as a Model to Study the Development of Non-Alcoholic SteatOhepatitis (NASH)
A study testing Liver resection to isolate cells in people with NAFLD, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- NAFLD
- What is being tested?
- Liver resection to isolate cells
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 60 participants
- Where
- 1 siteItaly
- Study dates
- 1 Jul 2021to 31 Jul 2032
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site, 1 recruiting
- Recruiting
Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico - Istituto di Ricovero e Cura a Carattere Scientifico di natura pubblica
Milan, Milano, 20122
Luca Vittorio Carlo Valenti, 02 5503 6595 ext. 56595, luca.valenti@policlinico.mi.it
About this study
Official title: Human Liver ORganoids as a Model to Study the Role of the I148M Variant of the PNPLA3 Gene in the Development of Non-Alcoholic SteatOhepatitis (NASH)
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
Read the detailed description
Non-alcoholic fatty liver disease (NAFLD) represents the main cause of liver damage and is found in approximately one third of the population (25-30%). NAFLD encompasses a broad spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH is found in 20-30% of patients with NAFLD and can progress to cirrhosis and hepatocellular carcinoma.
Progress recorded in recent years in the field of genetics has highlighted how genetic factors play a key role in the susceptibility, severity and long-term prognosis of the disease. In particular, in a genome-wide association study conducted on a multi-ethnic population, the PNPLA3 gene was identified as the main genetic factor that is strongly associated with intra-hepatic fat content, independently of body mass and insulin resistance.
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
- Being tested
- Liver resection to isolate cells
- Medical subject headings
- Non-alcoholic Fatty Liver Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Liver resection to isolate cellsGenetic
Isolation and culture of organoids Isolation of hepatic stellate cells Isolation and culture of sinusoidal stellate cells Generation of assembloids
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: Genetic: Liver resection to isolate cells |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
Measured: up to 35 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Mar 2025
- Study start1 Jul 2021
- Primary completion31 Jul 2030 (estimated)
- Study completion31 Jul 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NAFLDStudies of the same condition, open and under way.
- More trials run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- 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.
- Masking
- None (open label)
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Luca Valenti:, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06856252
- Sponsor's protocol ID
- REASON
- Acronym
- REASON
- Status last verified
- Nov 2025
- First submitted
- 8 Mar 2024
- Last updated
- 20 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 20 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Human Liver ORganoids as a Model to Study the Role of the I148M Variant of the PNPLA3 Gene in the Development of Non-Alcoholic SteatOhepatitis (NASH)
- ClinicalTrials.gov ID
- NCT06856252
- Acronym / sponsor ID
- REASON / REASON
- Conditions
- NAFLD
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoUniversity, hospital or other
- Study start
- 1 Jul 2021 (actual)
- Primary completion
- 31 Jul 2030 (estimated)
- Study completion
- 31 Jul 2032 (estimated)
- First posted
- 4 Mar 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Detailed description
Non-alcoholic fatty liver disease (NAFLD) represents the main cause of liver damage and is found in approximately one third of the population (25-30%). NAFLD encompasses a broad spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). NASH is found in 20-30% of patients with NAFLD and can progress to cirrhosis and hepatocellular carcinoma.
Progress recorded in recent years in the field of genetics has highlighted how genetic factors play a key role in the susceptibility, severity and long-term prognosis of the disease. In particular, in a genome-wide association study conducted on a multi-ethnic population, the PNPLA3 gene was identified as the main genetic factor that is strongly associated with intra-hepatic fat content, independently of body mass and insulin resistance.
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
Study design
- Primary purpose
- Prevention
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- 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.
| Arm | Type | Receives |
|---|---|---|
| Liver resection to isolate cells | Experimental | Genetic: Liver resection to isolate cellsIsolation and culture of organoids Isolation of hepatic stellate cells Isolation and culture of sinusoidal stellate cells Generation of assembloids |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Liver resection to isolate cellsIsolation 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 |
Primary outcome
Generation of treatment-related assembloids
Time frame: up to 35 months
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
Rate of PNPLA3 p.I148M variant in steatohepatitis development through human liver organoids
Time frame: up to 35 months
* 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
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Nov 2025.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Liver resection to isolate cells in people with NAFLD, run by Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 20 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Luca Vittorio Carlo Valenti (02 5503 6595 ext. 56595, luca.valenti@policlinico.mi.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Generation of treatment-related assembloids (time frame: up to 35 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Nov 2025.