NCT03887169

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

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

• Status: Completed
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 3 (actual)
• Sponsor: Assistance Publique - Hôpitaux de Paris · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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

Interventions

Type	Name	Description
DRUG	Methionine	Administration of methionine from D1 to D60
DRUG	Vitamin B12, B9, B6, C supplementation	In case of hyperhomocysteinemia
DIAGNOSTIC_TEST	Methionine/homocysteine Dosage	Plasma concentration control of methionine and homocysteine from D0 to D75
DIAGNOSTIC_TEST	Thoracic CT scan	At D60
DIAGNOSTIC_TEST	Abdominal and liver ultrasound.	At D60
DIAGNOSTIC_TEST	Brain MRI	In case of abnormal neurological examination

Timeline

• Start date: 2019-09-16
• Primary completion: 2020-06-01
• Completion: 2020-06-01
• First posted: 2019-03-22
• Last updated: 2025-11-20

Locations

1 site across 1 country: France