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

Adrenoleukodystrophy Clinical Trial

— MATRIX  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04925349
• Other study ID #: APHP190197
• Status: Recruiting
• Start date: August 30, 2021
• Est. completion date: February 2025

Study information

• Verified date: January 2024
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Fanny MOCHEL
• Phone: 01 57 27 44 82
• Email: fanny.mochel[@]icm-institut.org
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 56
• Est. completion date: February 2025
• Est. primary completion date: August 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 15 Months to 60 Years

Eligibility

Inclusion Criteria:

• Boys or girls aged between 15 months and 18 years (inclusive) diagnosed with MLD (low ARSA activity and accumulation of sulfatides in urine)

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

• 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)

• Adult males aged between 18 and 60 diagnosed with AMN (elevated VLCFA and clinical symptoms of AMN without leukodystrophy at brain MRI)

• Adult male aged between 18 and 60 diagnosed with CALD (elevated VLCFA with leukodystrophy at brain MRI)

• Adult male or female between 18 and 60 diagnosed with ALSP (CSF1R mutation and leukodystrophy at brain MRI)

• Children (15 months-18 years) without neurologic disease (no obvious neurological symptoms, normal neurologic examination)

• Informed consent obtained :

• from the parents or guardian for children patients and children controls ;

• from subject himself for adult patients.

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

Related Conditions & MeSH terms

• Adrenoleukodystrophy
• Adrenomyeloneuropathy
• Leukodystrophy, Metachromatic
• Leukoencephalopathies
• Metachromatic Leukodystrophy

Intervention

Diagnostic Test:
• Blood sample collection
blood sample collection

Locations

Country	Name	City	State
France	AP-HP Hôpital Bicêtre	Le Kremlin-Bicêtre
France	AP-HP Hôpital La Pitié Salpêtrière	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

References & Publications (4)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Macrophages functionality - myelin phagocytosis capacity	percentage of myelin high, myelin low and myelin negative cells using flow cytometry	2 years after blood collection
Primary	Macrophages functionality - HLA levels	maximum fluorescence intensity for HLA markers using flow cytometry	2 years after blood collection
Secondary	Macrophages metabolic profiling	Macrophages metabolic profiling (>2000 metabolites) using liquid chromatography coupled to high resolution mass spectrometry	2 years after blood collection
Secondary	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