Target of Suv420h1/2 in Hepatocytes
ConditionNAFLD
Trial statusRecruiting
Trial phaseNot applicable
Trial typeInterventional
Biological sexAll
Age18+
SponsorFondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
About this trial
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.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
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.
Diagnosis of NAFLD
Disqualifiers
Individuals not reporting one of the inclusion criteria listed above or reporting at-risk alcohol intake (>30/20 g/day in M/F), viral and autoimmune hepatitis or other causes of liver disease will be ex- cluded.
Trial design
Design model
Single group
Treatments tested in this trial
the main genes and expression by comparing the transcriptomic lipidomic profile
Diagnostic testTo identify the main genes and pathways differentially expressed and the main factors associ- ated in order to evaluate the role of SUV420H1/H2
Treatment groups
260 Participants
are divided into 1 treatment groupGroup A: the main genes and expression by comparing the transcriptomic lipidomic profileExperimental treatment 1 intervention
Trial outcomes
Primary outcomes
1
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).
Time frame
up to 30 mounths2
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).
Time frame
up to 30 mounthsSponsors and contacts
Click on the lead sponsor to view all of their trials.
Source ClinicalTrials.gov