Clinical trial NCT03887169: Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
Official title: Oral or Enteral Administration of Methionine in Patients With Pulmonary Alveolar Proteinosis by Mutation of the MARS Gene.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Pulmonary Alveolar Proteinosis
Mutation Ala393Thr of the MARS Gene
mutationSer567Leu of the MARS Gene
Keywords: Pulmonary alveolar proteinosis
MARS gene
methionine
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2019-03-22
Enrollment: 3
Sex: ALL
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Tolerance Assessment
timeFrame: From day 0 to day 75
Secondary outcomes:
measure: Respiratory rate (cycles /min)
timeFrame: At day 0, day 15, day 30, day 45, day 60, day 75
measure: Oxygen need (L/min)
timeFrame: At day 0, day 15, day 30, day 45, day 60, day 75
measure: Respiratory signs of struggle
timeFrame: At day 0, day 15, day 30, day 45, day 60, day 75
measure: Lung lesions
timeFrame: At Day 60
measure: Lipo-proteinaceous material
timeFrame: At each bronchial-alveolar washes during the 2,5 months
measure: Weight
timeFrame: At Day 15, Day 30, Day 45, Day 60, Day 75
measure: mid upper arm circumference / head circumference rapport
timeFrame: At Day 15, Day 30, Day 45, Day 60, Day 75
measure: Hepatomegaly
timeFrame: At Day 0, Day 15, Day 30, Day 45, Day 60, Day 75
measure: cholestasis and hepatic cytolysis
timeFrame: At Day 0, Day 15, Day 30, Day 60, Day 75
measure: Hepatomegaly
timeFrame: At Day 0 and Day 60
measure: C reactive protein
timeFrame: At Day 0, Day 30, Day 60
measure: sedimentation rate
timeFrame: At Day 0, Day 30, Day 60
measure: Immunoglobulin G level
timeFrame: At Day 0, Day 30, Day 60
measure: Haemoglobin level
timeFrame: At Day 0, Day 30, Day 60
measure: Plasma concentration of methionine
timeFrame: From Day 0 to Day 75
measure: Plasma concentration of homocysteine
timeFrame: From Day 0 to Day 75
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Necker-Enfants Malades
state: Ile De France
Study officials:
affiliation: Hospital Necker Enfants Malades
name: Alice HADCHOUEL, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.