Target of Suv420h1/2 in Hepatocytes

NCT06332677 | Recruiting

• 1 other identifier: TERS
• Study Type: interventional
• Target: 260
• Locations: 1 country
• Sites: 1

Brief Summary

Nonalcoholic fatty liver disease (NAFLD) is globally the leading cause of liver disease and frequently progresses to cirrhosis and liver cancer. The identification of effective drugs is the main unmet clinical need. Changes in liver histones methylation accompanies the development and progression of NAFLD. Our preliminary data demonstrate that inactivation of the methyltransferases SUV420H1/2 in hepatocytes protects mice against NAFLD. In this project we propose to examine the relevance of these findings by evaluating the impact of genetic deletion of hepatic SUV420H1/2 in mice fed a steatogenic diet. To further evaluate the potential for clinical translation of these results, we will next 1) evaluate the expression of SUV420H1/2 in human liver transcriptomic data and 2) analyze the impact of genetic variations on disease outcomes in population-based cohorts; 3) test an innovative therapeutic approach based on hepatocyte-targeted antisense oligonucleotides downregulating SUV420H1/2 in human liver organoids/assembloids.

Conditions

NAFLD

Keywords

epigenetic

Outcome Measures

Primary Outcomes (2)

• the main genes and expression by comparing the transcriptomic lipidomic profile

  The primary aim is the identification of biological pathways differentially ex- pressed in NAFLD individuals. Considering the large number of individuals with severe liver disease in the NAFLD PERSPECTIVE and MAFALDA cohorts (n= 500) and the large size of UKBB population-based cohort (n=350,000 for common variants and n=200,000 for rare variants), for variants with a minor allele frequency (MAF) \>0.01, we estimated that the study has a power \>80% to detect six-fold difference in the risk of severe NAFLD in the PERSPECTIVE/MAFALDA, a 1.8% difference in the NAFLD prevalence (UK Biobank), and 4.4% difference in the liver fat content as measured by PDFF (UK Biobank) between carriers and non-carriers (Aim A and B).

  up to 30 mounths

• the main genes and expression by comparing the transcriptomic lipidomic profile

  The identification of a correlation between genotype influencing the SUV420H1/2 pathway and NAFLD phenotype. Reduction of intracellular fat accumulation, collagen accumulation and inflammation in terms of TNFalpha mRNA expression levels. In case of positive results from SUV420H1/H2 downregulation by antisense technology, both in mouse models than in human liver organoids and assembloids, we will submit a patent request for the human anti-SUV420H1-H2 ASO for the treatment of steatohepatitis (Fondazione IRCCS Ca' Granda and San Raffaele Institute).

  up to 30 mounths

Study Arms (1)

the main genes and expression by comparing the transcriptomic lipidomic profile

EXPERIMENTAL

To identify the main genes and pathways differentially expressed and the main factors associ- ated with SUV420H1/H2 expression by comparing the transcriptomic and lipidomic profile of indi- viduals with low hepatic SUV420H1/H2 mRNA expression levels (lowest expression quartile) to that from individuals with high expression levels (top quartile). In order to evaluate the role of SUV420H1/H2 in the regulation of gene expression in NAFLD pa- tients, we will exploit already available transcriptomic and lipidomic data by analyzing the gene ex- pression databases deriving from ongoing studies conducted at the Fondazione and by the PI of the Catanzaro collaborating centre. Data have been generated from liver and visceral adipose biopsy of obese individuals at high risk of developing NASH (SERENA Study at Fondazione, and MAFALDA Study, coordinated by prof Stefano Romeo, PI of the Università Magna Graecia Catanzaro).

Diagnostic Test: the main genes and expression by comparing the transcriptomic lipidomic profile

Interventions

the main genes and expression by comparing the transcriptomic lipidomic profile DIAGNOSTIC_TEST

To identify the main genes and pathways differentially expressed and the main factors associ- ated in order to evaluate the role of SUV420H1/H2

the main genes and expression by comparing the transcriptomic lipidomic profile

Eligibility Criteria

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

You may qualify if:

• We will analyse data and samples from subjects with the following criteria:
• Subjects aged\>18;
• Subjects who have already given their consent to genetic analysis and whose samples and data have already been collected as part of the SERENA, REASON and MAFALDA studies;
• Subjects who have given their consent to participate in this study.
• In particular, subjects with the following characteristics were included respectively:
• in the SERENA study:
• Diagnosis of NAFLD
• Age between 45 and 75 years old
• Any of the following criteria:
• F3-F4 fibrosis, determined histologically, or by non-invasive techniques, or evidence of cirrhosis deriving from biochemical tests or imaging methods;
• Family history of related first-degree primary liver cancer, or carrier status of rare mutations associated with the development of HCC (such as mutations in APOB and TERT)
• Male patient with type 2 diabetes or obesity carrying at least three genetic variants in PNPLA3, TM6SF2, MBOAT7.
• in the REASON study:
• Patients aged\>18, who have given their consent to participate in the study, who underwent the fol- lowing procedures:
• liver biopsy for suspected non-alcoholic steatohepatitis (NASH) at the time of diagnosis;

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, 20122, Italy

RECRUITING

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease

Condition Hierarchy (Ancestors)

Fatty Liver; Liver Diseases; Digestive System Diseases

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: study the cellular and molecular mechanisms of correlation between the SUV420H1/H2 methyltransferase and the progression of liver damage in mice (San Raffaele Institute) and to confirm these findings in human samples and in vitro 3D liver models.

Study Record Dates

• First Submitted: March 8, 2024
• First Posted: March 27, 2024
• Study Start: March 1, 2023
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): April 30, 2027
• Last Updated: March 27, 2026

Record last verified: 2026-03

Locations

IT (1)