Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.

NCT ID: NCT03887169

Last Updated: 2025-11-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 3 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-09-16
• Study Completion Date: 2020-06-01

Brief Summary

The purpose of this study is to determine the safety and tolerance of an oral administration of methionine in the treatment of pulmonary alveolar proteinosis due to the double mutation Ala393Thr / Ser567Leu in the MARS gene. This disease is very severe and especially leads to chronic respiratory insufficiency. There is no curative treatment for this disease. The MARS gene encodes the methionine tRNA synthetase (MetRS). Mutations in this gene leads to a defect in MetRS function. In cultured mutated yeast, addition of methionine in culture medium restores MetRS function. Therefore, the investigators hypothesized that treatment of patients with methionine could have beneficial effects on the disease.

Detailed Description

Pulmonary alveolar proteinosis (PAP) is a rare respiratory disorder. Recently, a genetic cause has been identified for a specific form of PAP predominant on La Reunion Island. This form is characterized by a multisystem phenotype including PAP, failure to thrive, hepatic involvement and chronic inflammation. This is a severe disease without any specific treatment and a high rate of mortality related to end-stage respiratory insufficiency. Two recurrent mutations were isolated in the MARS gene that encodes the methionine tRNA synthetase (MetRS). This enzyme catalyzes the ligation of methionine to tRNA and is critical for protein biosynthesis. Functional studies on mutated yeast show an altered growth and protein synthesis as compared to control yeast. Addition of methionine in culture medium corrects these defects. Complementary experiments on human purified MetRS show altered enzymatic catalytic parameters in mutated forms. Increasing blood concentration of methionine in patients could correct these parameters and potentially improve patients' phenotype in this severe disorder where no curative treatment exists.

The main objective of this protocol is to determine the tolerance of a prolonged daily supplementation of methionine in patients presenting a MARS related PAP. The secondary objectives are to determine the efficiency of such treatment on respiratory, hepatic, inflammatory and growth status.

To meet the objectives of the study, enrolled patients will receive daily oral or enteral methionine administration at increasing doses, under surveillance of plasma levels of methionine and homocysteine, and possible clinical side effects, until determining the "ideal" dose for each patient.

Once daily dosage determined for each patient, this dosage will be continued for a total of 2 months with daily clinical monitoring of tolerance and bi-monthly plasma levels surveillance of methionine and homocysteine.

Conditions

Pulmonary Alveolar Proteinosis; Mutation Ala393Thr of the MARS Gene; mutationSer567Leu of the MARS Gene

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Methionine

Group Type: EXPERIMENTAL

Methionine

Intervention Type: DRUG

Administration of methionine from D1 to D60

Vitamin B12, B9, B6, C supplementation

Intervention Type: DRUG

In case of hyperhomocysteinemia

Methionine/homocysteine Dosage

Intervention Type: DIAGNOSTIC_TEST

Plasma concentration control of methionine and homocysteine from D0 to D75

Thoracic CT scan

Intervention Type: DIAGNOSTIC_TEST

At D60

Abdominal and liver ultrasound.

Intervention Type: DIAGNOSTIC_TEST

At D60

Brain MRI

Intervention Type: DIAGNOSTIC_TEST

In case of abnormal neurological examination

Interventions

Methionine

Administration of methionine from D1 to D60

Intervention Type: DRUG

Vitamin B12, B9, B6, C supplementation

In case of hyperhomocysteinemia

Intervention Type: DRUG

Methionine/homocysteine Dosage

Plasma concentration control of methionine and homocysteine from D0 to D75

Intervention Type: DIAGNOSTIC_TEST

Thoracic CT scan

At D60

Intervention Type: DIAGNOSTIC_TEST

Abdominal and liver ultrasound.

At D60

Intervention Type: DIAGNOSTIC_TEST

Brain MRI

In case of abnormal neurological examination

Intervention Type: DIAGNOSTIC_TEST

Eligibility Criteria

Inclusion Criteria

• Minor Patient with alveolar proteinosis by double mutation Ala393Thr and SER567LEU of the MARS gene, genetically proven.
• Patient in need of prolonged hospitalization in Necker for treatment of bronchial-alveolar washes in the context of care.
• Patient for which methionine can be administered orally or by enteral probe (Nasogastric or gastrostomy probe)
• Signed Informed consent form by parents / legal guardian

Exclusion Criteria

• Patient with alveolar proteinosis by other mutations of the MARS gene
• Patient with alveolar proteinosis secondary to another etiology or without identified cause
• Refusal to participate in the study
• High blood pressure requiring drug treatment
• Heart failure
• Known hypersensitivity to one of the substances used or potentially used in the study: methionine, vitamins B6, B12, B9 and C
• Pre-Hypermethioninemia (Methioninemia > + 2 DS of normal for age) whatever the cause

• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

URC-CIC Paris Descartes Necker Cochin

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Alice HADCHOUEL, PhD

Role: PRINCIPAL_INVESTIGATOR

Hospital Necker Enfants Malades

Locations

Hôpital Necker-Enfants Malades

Paris, Île-de-France Region, France

Countries

France

References

Hadchouel A, Drummond D, Pontoizeau C, Aoust L, Hurtado Nedelec MM, El Benna J, Gachelin E, Perisson C, Vigier C, Schiff M, Lacaille F, Molina TJ, Berteloot L, Renolleau S, Ottolenghi C, Treluyer JM, de Blic J, Delacourt C. Methionine supplementation for multi-organ dysfunction in MetRS-related pulmonary alveolar proteinosis. Eur Respir J. 2022 Apr 21;59(4):2101554. doi: 10.1183/13993003.01554-2021. Print 2022 Apr.

Reference Type: RESULT

PMID: 34503986 (View on PubMed)

Other Identifiers

2018-004140-28

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

DC20180338

Identifier Type: -

Identifier Source: org_study_id