Assessment of microRNAs Role in Familial Mediterranean Fever FMF Pathophysiology (miRinFMF)
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ClinicalTrials.gov Identifier: NCT06033339 |
Recruitment Status :
Not yet recruiting
First Posted : September 13, 2023
Last Update Posted : September 14, 2023
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Tracking Information | |||||
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First Submitted Date ICMJE | September 5, 2023 | ||||
First Posted Date ICMJE | September 13, 2023 | ||||
Last Update Posted Date | September 14, 2023 | ||||
Estimated Study Start Date ICMJE | October 2, 2023 | ||||
Estimated Primary Completion Date | October 2, 2025 (Final data collection date for primary outcome measure) | ||||
Current Primary Outcome Measures ICMJE |
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Original Primary Outcome Measures ICMJE | Same as current | ||||
Change History | |||||
Current Secondary Outcome Measures ICMJE |
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Original Secondary Outcome Measures ICMJE | Same as current | ||||
Current Other Pre-specified Outcome Measures | Not Provided | ||||
Original Other Pre-specified Outcome Measures | Not Provided | ||||
Descriptive Information | |||||
Brief Title ICMJE | Assessment of microRNAs Role in Familial Mediterranean Fever FMF Pathophysiology | ||||
Official Title ICMJE | Etude du rôle Des microARNs Dans la Physiopathologie de la fièvre méditerranéenne Familiale | ||||
Brief Summary | Familial Mediterranean Fever (FMF) genetic diagnosis is well established for homozygous patients. On the other hand, although heterozygous individuals are theoretically healthy carriers, 1/3 of them will develop clinical symptoms of FMF and could benefit from prophylactic treatment. This suggests that the disorder expression mechanisms are not fully elucidated to date. The preliminary results obtained at the Institute for Regenerative Medicine and Biotherapy (IRMB) suggest the involvement of an epigenetic mechanism in FMF pathogenesis, and our laboratory has strong arguments as to the involvement of microRNAs (in particular miR-326) which are negative regulators of gene expression. This study is exploratory and aims to validate the role of miRNAs in the clinical expression of FMF in patients, thus to explore the epigenetic mechanisms that may explain the variability of expression of this disorder. |
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Detailed Description | Familial Mediterranean fever (FMF) is a rare autoinflammatory disorder due to mutations in the MEFV (MEditerranean FeVer) gene, that causes recurrent episodes of fever and acute serositis (peritoneum, pleura, synovium) beginning in early childhood. MEFV gene identification allowed the development of a genomic sequencing test to confirm the diagnosis. The most frequent mutations are M680I, M694V, V726A and M694I, located in exon 10. This gene encodes the protein pyrin, which, following a pro-inflammatory stimulus, is capable of assembling a multi-protein complex to form the pyrin inflammasome. MEFV gene mutations lead to an alteration of its expression in innate immune system cells in FMF patients, causing a dysregulation of the immune response, which results in the abnormal secretion of certain proinflammatory cytokines such as IL-1β and IL-18. FMF is an autosomal recessive disorder. Thus, heterozygous individuals are theoretically healthy carriers. Nevertheless, in nearly 1/3 of patients with clinical symptoms of FMF, a single heterozygous mutation is found. To date, there is no biological marker to distinguish heterozygous individuals who will develop the disease from those who remain healthy carriers, hence diagnostic errors and delays in treatment. Several hypotheses have been put forward to explain this variation in mutation expression, whether it is the environment, the involvement of other genes, or the involvement of epigenetic modifiers. Among the mechanisms that regulate gene expression, microRNAs (miRNAs),which are small non-coding RNAs, negatively regulate gene expression at the post-transcriptional level by binding to sequences located mainly in the region 3'UTR of gene mRNA. Many publications report that they are abnormally expressed in various pathologies. Very recently, this has been reported for FMF. Several studies have focused on miRNAs as biomarkers of FMF, without evaluating their role in FMF pathogenesis. Assessing the role of miRNAs specifically targeting the MEFV gene in myeloid cells (especially monocytes), and the functional impact of their modulation in these cells, would deepen our understanding of FMF physiopathology. If a miRNA specifically targeting MEFV has a proven role in FMF pathophysiology, it could ultimately prove to be a prognostic biomarker of the disorder for heterozygous patients, or even a future therapeutic target. |
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Study Type ICMJE | Interventional | ||||
Study Phase ICMJE | Not Applicable | ||||
Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Intervention Model Description: Among the 40 subjects to be enrolled: 10 are MEFV homozygous patients, 10 are symptomatic MEFV heterozygous patients, 10 are asymptomatic MEFV heterozygous patients and 10 are control subjects. All enrolled patients receive the same intervention (biological sample collection). Masking: None (Open Label)Primary Purpose: Other |
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Condition ICMJE | Familial Mediterranean Fever | ||||
Intervention ICMJE | Other: Blood sampling
Collection of 10 ml of blood on EDTA tubes per patient. Once collected, the blood tubes will be transported within 24 hours to the IRB (Biotherapy Research Institute) of Montpellier University Hospital, where the monocytes will be isolated by magnetic sorting on the basis of expression of surface marker CD14+, after a preliminary step of Ficoll. Monocytes will then be frozen in nitrogen at -196°C until use (biobank).Gain-of-function experiments will then be performed on monocytes by transfecting them with the microRNA of interest or control. The expression of the pyrin protein and its phosphorylation rate will be evaluated after induction by immunoprecipitation experiments followed by western blot. The activity of the pyrin inflammasome will also be studied by looking at pyroptosis and toxicity rate using LDH test. All these experiments will be carried out in the absence and in the presence of the microRNA in order to study its role in the pathophysiology of FMF.
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Study Arms ICMJE | Blood Sampling
Collection of 10 ml of blood on EDTA tube during:
Intervention: Other: Blood sampling
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Publications * | Not Provided | ||||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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Recruitment Information | |||||
Recruitment Status ICMJE | Not yet recruiting | ||||
Estimated Enrollment ICMJE |
40 | ||||
Original Estimated Enrollment ICMJE | Same as current | ||||
Estimated Study Completion Date ICMJE | October 2, 2025 | ||||
Estimated Primary Completion Date | October 2, 2025 (Final data collection date for primary outcome measure) | ||||
Eligibility Criteria ICMJE | Inclusion Criteria:
Exclusion Criteria:
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Sex/Gender ICMJE |
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Ages ICMJE | 1 Year and older (Child, Adult, Older Adult) | ||||
Accepts Healthy Volunteers ICMJE | Yes | ||||
Contacts ICMJE |
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Listed Location Countries ICMJE | France | ||||
Removed Location Countries | |||||
Administrative Information | |||||
NCT Number ICMJE | NCT06033339 | ||||
Other Study ID Numbers ICMJE | RECHMPL22_0296 - UF 8310 | ||||
Has Data Monitoring Committee | No | ||||
U.S. FDA-regulated Product |
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IPD Sharing Statement ICMJE |
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Current Responsible Party | University Hospital, Montpellier | ||||
Original Responsible Party | Same as current | ||||
Current Study Sponsor ICMJE | University Hospital, Montpellier | ||||
Original Study Sponsor ICMJE | Same as current | ||||
Collaborators ICMJE | Not Provided | ||||
Investigators ICMJE |
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PRS Account | University Hospital, Montpellier | ||||
Verification Date | September 2023 | ||||
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |