Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia (MATRIX)

MATRIX - "Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia"

This study is a national, non-randomized, open-label, multi-site with minimal risk study in adult with adrenomyeloneuropathy (AMN), childhood and adult subjects with cerebral ALD (cALD), juvenile/adult metachromatic leukodystrophy (MLD) and adults with leukoencephalopathy and axonal spheroids and pigmented glia (ALSP). 49 subjects will be enrolled with one blood sample collection during one of their medical follow-up visit.

This trial will evaluate the role of innate immunity to influence disease progression in X-ALD, MLD and ALSP, and if the mutations related to these leukodystrophies result in a specific immune response leading to the pathogenesis.

Study Overview

• Status: Recruiting
• Conditions: Adrenoleukodystrophy; Adrenomyeloneuropathy; Metachromatic Leukodystrophy; Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
• Intervention / Treatment: Diagnostic test: Blood sample collection

Detailed Description

X-linked Adrenoleukodystrophy (X-ALD), Metachromatic Leukodystrophy (MLD) and Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) are among the most frequent inherited leukodystrophies. X-ALD and MLD can affect both children and adults, while it is thought that ALSP onset exclusively during adulthood. These three diseases are characterized by phenotypic variability and poor genotype-phenotype correlation. In childhood forms of MLD and childhood cerebral ALD (C-CALD) a devastating cerebral demyelination and neuronal degeneration lead to a rapid neurologic degradation and premature death. Patients with the adult form of X-ALD (adrenomyeloneuropathy (AMN), 60% of males) display a progressive spastic paraplegia without brain involvement. However, 20% of AMN patients will also develop cerebral ALD. Patients diagnosed with the juvenile/adult (JA-) MLD form are affected by a progressive decline of their cognitive function, followed later by that of the motor abilities. ALSP patients present a rapidly progressive neurodegenerative disorder that impairs behavioural, cognitive and motor functions.

Several arguments support the contribution of the immune response and neuroinflammation in these three leukodystrophies. In X-ALD, activation of microglia (macrophages of the CNS) plays an essential role in the acute demyelination phase, where a severe inflammatory process occurs. In ALSP, the dysfunctional protein (CSF1R) is almost exclusively expressed in microglia. Even if MLD is not considered as a neuroinflammatory disease per se, microglia activation and increased inflammatory cytokines are observed in the brain of MLD patients and mice. Even if the most commonly accepted hypothesis is that neuroinflammation is caused by secondary activation of microglia following phagocytosis of myelin debris full of undegraded material, a primitive role of the inflammation due to macrophages (MAC) dysfunction has emerged in recent years.

MATRIX proposes to explore how disease-related mutations affect key components of MAC activation responses and how it reflects on their functionality.

• Study Type: Observational
• Enrollment (Estimated): 100

Contacts and Locations

• Study Contact: Name: Christelle AUGER; Email: christelle.auger@aphp.fr
• Study Contact Backup: Name: Fanny MOCHEL; Phone Number: 01 57 27 44 82; Email: fanny.mochel@icm-institut.org

Study Locations

• France
  • Le Kremlin-Bicêtre, France, 94275
    • Recruiting
    • AP-HP Hôpital Bicêtre
    • Contact: Caroline SEVIN, MD-PhD; Phone Number: +33 1 45 21 30 17; Email: caroline.sevin@inserm.fr
    • Principal Investigator: Fanny MOCHEL, MD-PhD
    • Sub-Investigator: Caroline SEVIN, MD-PhD
    • Contact: Fanny MOCHEL, MD-PhD; Phone Number: +33 1 5727 44 82; Email: fanny.mochel@icm-institut.org
  • Paris, France, 75013
    • Recruiting
    • AP-HP Hôpital La Pitié Salpêtrière

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 60 years (Child, Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Probability Sample

Study Population

Pediatric and adult populations. Both affected (C-CALD, AMN, A-CALD, MLD, ALSP), presymptomatic children carrying ABCD1 mutations (PRE-ALD), presymptomatic patient adults carrying CSF1R mutations (PRE-ALSP) and age-matched control subjects will be enrolled (N=10/group). Minor subjects (C-CALD, MLD, PRE-ALD and controls) will be included, based on childhood onset of C-CALD and MLD

Description

Inclusion Criteria:

Boys aged between 3 and 18 years (inclusive) diagnosed with C-CALD (elevated levels of VLCFA and leukodystrophy at brain MRI)

• Boys or girls aged between 15 months and 18 years (inclusive) diagnosed with MLD (low ARSA activity and accumulation of sulfatides in urine)
• Presymptomatic boys carrying ABCD1 mutations aged between 3 and 18 years (inclusive) (PRE-ALD)
• Adult males or females aged between 18 and 60 diagnosed with MLD (low ARSA activity and accumulation of sulfatides in urine)
• Males aged between 18 and 60 years diagnosed with AMN (elevated VLCFA and clinical symptoms of AMN without leukodystrophy at brain MRI)
• Males aged between 18 and 60 years diagnosed with CALD (elevated VLCFA with leukodystrophy at brain MRI)
• Adult males or females aged between 18 and 60 years diagnosed with ALSP (CSF1R mutation and leukodystrophy at brain MRI)
• Presymptomatic patient adults (males or females) carrying CSF1R mutations (PRE-ALSP)
• Children (15 months-18 years) without neurologic disease (no obvious neurological symptoms, normal neurologic examination)
• Adults aged between 18 and 60 years without neurologic disease (no overt neurological symptoms)
• Informed consent obtained :
• from the parents or guardian for children patients and children controls;
• from subject himself for adult patients and adult controls.

Exclusion Criteria:

• Participation to a therapeutic clinical trial
• Treatment likely to modify the immune system
• Unable to have a blood collection (i.e. low hemoglobin level at the investigator's judgment)
• Any other reason, to the discretion of the investigator
• Children or adults without health insurance or social security

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
affected subjects; adult patients with adrenomyeloneuropathy/adrenoleukodystrophy; children with adrenoleukodystrophy; children with metachromatic leukodystrophy	Diagnostic test: Blood sample collection; blood sample collection
control subjects; healthy children; heatthy adults	Diagnostic test: Blood sample collection; blood sample collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrophages functionality - distribution of monocytes	distribution of monocytes in the CD14-/+/++ and CD16-/+ classification using flow cytometry (% of CD14++/16-; CD14++/16+; CD14+/16+; CD14-/16-)	2 years after blood collection
Macrophages functionality - myelin phagocytosis capacity	percentage of myelin high, myelin low and myelin negative cells using flow cytometry	2 years after blood collection
Macrophages functionality - HLA levels	maximum fluorescence intensity for HLA markers using flow cytometry	2 years after blood collection

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Macrophages metabolic profiling	Macrophages metabolic profiling (>2000 metabolites) using liquid chromatography coupled to high resolution mass spectrometry	2 years after blood collection
Macrophages transcriptomic profiling	Macrophages transcriptomic profiling (>1200 coding and non coding genes) : RNA sequencing using NextSeq 500 Illumina (60 million single-end, 150 base reads ) and analysis (using FastQC, Picard-Tools, Samtools and rseqc softwares	2 years after blood collection

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin
• Investigators: Principal Investigator: Fanny MOCHEL, MCU-PH, Institut du Cerveau et de la Moelle Epinière; Study Chair: Violetta ZUJOVIC, PhD, CR1, Institut du Cerveau et de la Moelle Epinière; Study Director: Caroline SEVIN, PhD, Kremlin Bicêtre Hôpital

Publications and helpful links

General Publications

• Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL, van Wijngaarden P, Wagers AJ, Williams A, Franklin RJM, Ffrench-Constant C. M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci. 2013 Sep;16(9):1211-1218. doi: 10.1038/nn.3469. Epub 2013 Jul 21.
• Weinhofer I, Zierfuss B, Hametner S, Wagner M, Popitsch N, Machacek C, Bartolini B, Zlabinger G, Ohradanova-Repic A, Stockinger H, Kohler W, Hoftberger R, Regelsberger G, Forss-Petter S, Lassmann H, Berger J. Impaired plasticity of macrophages in X-linked adrenoleukodystrophy. Brain. 2018 Aug 1;141(8):2329-2342. doi: 10.1093/brain/awy127.
• Berger J, Forss-Petter S, Eichler FS. Pathophysiology of X-linked adrenoleukodystrophy. Biochimie. 2014 Mar;98(100):135-42. doi: 10.1016/j.biochi.2013.11.023. Epub 2013 Dec 4.
• Gieselmann V, Krageloh-Mann I. Metachromatic leukodystrophy--an update. Neuropediatrics. 2010 Feb;41(1):1-6. doi: 10.1055/s-0030-1253412. Epub 2010 Jun 22.

Study record dates

Study Major Dates

• Study Start (Actual): August 30, 2021
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: April 15, 2019
• First Submitted That Met QC Criteria: June 7, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Estimated): September 24, 2025
• Last Update Submitted That Met QC Criteria: September 18, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: Neuroinflammation; Nervous System Diseases; Leukodystrophy; Central Nervous System Diseases; Immune system
• Additional Relevant MeSH Terms: Neurologic Manifestations; Endocrine System Diseases; Brain Diseases; Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Neurobehavioral Manifestations; Inflammation; Demyelinating Diseases; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Adrenal Gland Diseases; Intellectual Disability; Genetic Diseases, X-Linked; Lysosomal Storage Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Adrenal Insufficiency; Sulfatidosis; Peroxisomal Disorders; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; X-Linked Intellectual Disability; Neuroinflammatory Diseases; Nervous System Diseases; Central Nervous System Diseases; Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Hereditary Diffuse Leukoencephalopathy with Spheroids
• Other Study ID Numbers: APHP190197; IDRCB (Registry Identifier: 2022-A02601-42)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No