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Impact of Mutations in Aminoacyl tRNA Synthetases on Protein Translation and Cellular Stress

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	N/A and Over
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- 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.

Exclusion Criteria:

- 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 Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05514470
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	N/A
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	Assistance Publique - Hôpitaux de Paris
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Alice HADCHOUEL, MD, PhDIsabelle SERMET-GAUDELUS, MD, PhD
Principal Investigator Affiliation	Assistance Publique - Hôpitaux de ParisAssistance Publique - Hôpitaux de Paris
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other
Overall Status	Not yet recruiting
Countries	France
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	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

Additional Details

- 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.

Arms & Interventions

Arms

Experimental: Patients

Patients with mutations in genes encoding cytosolic aminoacyl-tRNA synthetases and cared at Necker Hospital.

Interventions

Other: - Skin biopsy

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.

Contact a Trial Team

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