Interstitial Lung and Liver DiseaseFIBROMARSNCT05514470
Impact of Mutations in Aminoacyl tRNA Synthetases on Protein Translation and Cellular Stress
A study testing Skin biopsy in people with Interstitial Lung and Liver Disease and Infantile Liver Failure Syndrome 1, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
Trial summary
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease, liver damage, neurological and digestive disorders, and systemic inflammation. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Interstitial Lung and Liver Disease, Infantile Liver Failure Syndrome 1, Neurologic, Endocrine and Pancreatic Disease, Multisystem, Infantile-Onset 2
- What is being tested?
- Skin biopsy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteFrance
- Study dates
- Nov 2024to Nov 2027
- Phase
- Interventional
- Are there results?
- None posted in the registry
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 Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- Patients carrying mutations in genes encoding cytosolic aminoacyl-tRNA synthetases responsible for a multi-systemic phenotype
- Information and consent of the patient if an adult and of the holders of parental authority if a minor patient and of the minor patient
Who cannot join
- Non-consent of one of the holders of parental authority or of the minor patient or of adult patient
- Contrôl patients :
- Fibroblasts from control patients without mutation in genes encoding cytosolic aminoacyl-tRNA synthetases, from an existing biological collection. The control patients will be selected according to the age at which the skin biopsy was performed in order to have an age match between the patients and the controls.
- Information and consent of the patient if an adult and of the holders of parental authority if a minor patient and of the minor patient
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Impact of Loss-of-function Mutations of Genes Encoding Cytosolic Aminoacyl-tRNA Synthetases on Protein Translation and Responses to Cellular Stress
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease, liver damage, neurological and digestive disorders, and systemic inflammation. These are rare and severe diseases whose pathophysiology is poorly understood.
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation. The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid.
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation.
Read the detailed description
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease, liver damage, neurological and digestive disorders, and systemic inflammation. These are rare and severe diseases whose pathophysiology is poorly understood.
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation. The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid.
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation.
The parameters below will be studied in vitro in cell culture from skin biopsies of patients and control cells:
- Determination of total protein content
- The incorporation of d-methionine, leucine, tyrosine or phenylalanine into proteins
- The study of polysomes profiling
- The study of the assembly of the ribosomal 43S pre-initiation complex
- The phosphorylation of eIF2α and 4EBP and the expression of ATF4
- Ribosome profiling
- Transfer RNA (tRNA) sequencing
- The production of reactive oxygen species (ROS)
The results of these studies will be compared:
- Between patient cells and control cells
- Between genetically corrected patient cells, by stable transfection of the wild-type cDNA of the concerned genes and uncorrected cells
- Between patient cells cultured in medium enriched with the corresponding amino acid.
- Conditions
- Interstitial Lung and Liver Disease, Infantile Liver Failure Syndrome 1, Neurologic, Endocrine and Pancreatic Disease, Multisystem, Infantile-Onset 2, Rajab Interstitial Lung Disease With Brain Calcifications 2
- Being tested
- Skin biopsy
- Keywords
- Cytosolic aminoacyl-tRNA synthetase, Mutations in the MARS1 gene, Mutations in the LARS1 gene, Mutations in the YARS1 gene, Mutations in the FARSA gene
- Medical subject headings
- Liver Diseases, Neurologic Manifestations, Pancreatic Diseases
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Skin biopsyOther
A skin biopsy performed on the forearm or thigh depending on the patient's age and wishes, with a biopsy punch with a diameter of 3 to 4 mm depending on the child's age (3 for children under 3 years, 4 beyond).
Culture of fibroblasts and immortalization.
| Study group | Role | What they receive |
|---|---|---|
| Patients | Experimental | Patients with mutations in genes encoding cytosolic aminoacyl-tRNA synthetases and cared at Necker Hospital. Receives: Other: Skin biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Determination of total protein content
Determination of total protein content by Bicinchoninic acid assay.
Measured: Day 0
Incorporation of d-methionine and d-phenylalanine into proteins
Incorporation of methionine and phenylalanine by labelled amino-acid fluorescent assays using ready-to-use kits.
Measured: Day 0
Study of polysomes profiling
Study of polysome profils by differential sedimentation on sucrose gradients.
Measured: Day 0
Study of the assembly of the ribosomal 43S pre-initiation complex
Study of the assembly of the ribosomal 43S pre-initiation complex by co-immunoprecipitation experiments.
Measured: Day 0
Phosphorylation of eIF2α and 4EBP and the expression of ATF4
Phosphorylation of eIF2α and 4EBP and the expression of ATF4 by western blot.
Measured: Day 0
Ribosome profiling
Ribosome profiling by high throughput sequencing.
Measured: Day 0
Transfer RNA (tRNA) sequencing
Transfer RNA (tRNA) sequencing by high throughput sequencing.
Measured: Day 0
Production of reactive oxygen species (ROS)
Production of reactive oxygen species (ROS) by fluorescent measurement after cells' incubation with 2',7'- dichlorodihydrofluorescein diacetate (H2DCFDA).
Measured: Day 0
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Aug 2022
- Study startNov 2024 (estimated)
- Primary completionNov 2027 (estimated)
- Study completionNov 2027 (estimated)
Why it stopped: The study could not begin
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Interstitial Lung and Liver DiseaseStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe 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
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Responsible party
- Sponsor
- Investigators
- Alice HADCHOUEL, MD, PhD, Principal investigator, Assistance Publique - Hôpitaux de ParisIsabelle SERMET-GAUDELUS, MD, PhD, Study director, Assistance Publique - Hôpitaux de Paris
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05514470
- Sponsor's protocol ID
- APHP220276
- Other IDs
- 2024-A01311-46
- Acronym
- FIBROMARS
- Status last verified
- Sep 2025
- First submitted
- 17 Jun 2022
- Last updated
- 25 Sep 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Loss-of-function Mutations of Genes Encoding Cytosolic Aminoacyl-tRNA Synthetases on Protein Translation and Responses to Cellular Stress
- ClinicalTrials.gov ID
- NCT05514470
- Acronym / sponsor ID
- FIBROMARS / APHP220276
- Conditions
- Interstitial Lung and Liver Disease, Infantile Liver Failure Syndrome 1, Neurologic, Endocrine and Pancreatic Disease, Multisystem, Infantile-Onset 2, Rajab Interstitial Lung Disease With Brain Calcifications 2
- Keywords
- Cytosolic aminoacyl-tRNA synthetase, Mutations in the MARS1 gene, Mutations in the LARS1 gene, Mutations in the YARS1 gene, Mutations in the FARSA gene
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: The study could not begin
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Collaborators
- URC-CIC Paris Descartes Necker Cochin
- Study start
- Nov 2024 (estimated)
- Primary completion
- Nov 2027 (estimated)
- Study completion
- Nov 2027 (estimated)
- First posted
- 24 Aug 2022 (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.
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease, liver damage, neurological and digestive disorders, and systemic inflammation. These are rare and severe diseases whose pathophysiology is poorly understood.
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation. The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid.
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation.
Detailed description
Mutations in the genes encoding cytosolic aminoacyl-tRNA synthetases are responsible for early-onset multisystemic diseases including to varying degrees interstitial lung disease, liver damage, neurological and digestive disorders, and systemic inflammation. These are rare and severe diseases whose pathophysiology is poorly understood.
The investigative team hypothesizes that mutations within these genes are responsible for a decrease in protein translation and lead to a cellular stress response similar to that induced by amino acid deprivation. The investigative team also hypothesizes that these alterations could be corrected by high-dose supplementation in the culture medium of the corresponding amino acid.
The main objective of the study is to precisely determine the consequences of cytosolic aminoacyl-tRNA synthetase mutations at the cell level on protein translation.
The parameters below will be studied in vitro in cell culture from skin biopsies of patients and control cells:
- Determination of total protein content
- The incorporation of d-methionine, leucine, tyrosine or phenylalanine into proteins
- The study of polysomes profiling
- The study of the assembly of the ribosomal 43S pre-initiation complex
- The phosphorylation of eIF2α and 4EBP and the expression of ATF4
- Ribosome profiling
- Transfer RNA (tRNA) sequencing
- The production of reactive oxygen species (ROS)
The results of these studies will be compared:
- Between patient cells and control cells
- Between genetically corrected patient cells, by stable transfection of the wild-type cDNA of the concerned genes and uncorrected cells
- Between patient cells cultured in medium enriched with the corresponding amino acid.
Study design
- Primary purpose
- Basic science
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients | Experimental | Other: Skin biopsyPatients with mutations in genes encoding cytosolic aminoacyl-tRNA synthetases and cared at Necker Hospital. |
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- Patients carrying mutations in genes encoding cytosolic aminoacyl-tRNA synthetases responsible for a multi-systemic phenotype
- Information and consent of the patient if an adult and of the holders of parental authority if a minor patient and of the minor patient
Key exclusion criteria (4 listed)
- Non-consent of one of the holders of parental authority or of the minor patient or of adult patient
- Fibroblasts from control patients without mutation in genes encoding cytosolic aminoacyl-tRNA synthetases, from an existing biological collection. The control patients will be selected according to the age at which the skin biopsy was performed in order to have an age match between the patients and the controls.
- Information and consent of the patient if an adult and of the holders of parental authority if a minor patient and of the minor patient
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 |
|---|---|---|
| Skin biopsyA skin biopsy performed on the forearm or thigh depending on the patient's age and wishes, with a biopsy punch with a diameter of 3 to 4 mm depending on the child's age (3 for children under 3 years, 4 beyond). Culture of fibroblasts and immortalization. | Other | Patients |
Primary outcome
Determination of total protein content
Time frame: Day 0
Determination of total protein content by Bicinchoninic acid assay.
Incorporation of d-methionine and d-phenylalanine into proteins
Time frame: Day 0
Incorporation of methionine and phenylalanine by labelled amino-acid fluorescent assays using ready-to-use kits.
Study of polysomes profiling
Time frame: Day 0
Study of polysome profils by differential sedimentation on sucrose gradients.
Study of the assembly of the ribosomal 43S pre-initiation complex
Time frame: Day 0
Study of the assembly of the ribosomal 43S pre-initiation complex by co-immunoprecipitation experiments.
Phosphorylation of eIF2α and 4EBP and the expression of ATF4
Time frame: Day 0
Phosphorylation of eIF2α and 4EBP and the expression of ATF4 by western blot.
Ribosome profiling
Time frame: Day 0
Ribosome profiling by high throughput sequencing.
Transfer RNA (tRNA) sequencing
Time frame: Day 0
Transfer RNA (tRNA) sequencing by high throughput sequencing.
Production of reactive oxygen species (ROS)
Time frame: Day 0
Production of reactive oxygen species (ROS) by fluorescent measurement after cells' incubation with 2',7'- dichlorodihydrofluorescein diacetate (H2DCFDA).
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2025.
- Individual participant dataSharing planned: No
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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. This study is not recruiting at the moment.
Alice HADCHOUEL, MD, PhD principal investigator
Assistance Publique - Hôpitaux de Paris
Isabelle SERMET-GAUDELUS, MD, PhD study director
Assistance Publique - Hôpitaux de Paris
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Skin biopsy in people with Interstitial Lung and Liver Disease and Infantile Liver Failure Syndrome 1, run by Assistance Publique - Hôpitaux de Paris at 1 site in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. 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: withdrawn, as of the sponsor's last update on 25 Sep 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 France. 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?
The study was withdrawn before enrolling participants, so there are no results.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Determination of total protein content (time frame: Day 0). The study lists 8 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 25 Sep 2025.