Clinical trial NCT04925349: Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
Official title: MATRIX - "Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy, Metachromatic Leukodystrophy and Adult Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia"
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Adrenoleukodystrophy
Adrenomyeloneuropathy
Metachromatic Leukodystrophy
Adult-Onset Leukoencephalopathy With Axonal Spheroids and Pigmented Glia
Keywords: Leukodystrophy
Central Nervous System Diseases
Nervous System Diseases
Immune system
Neuroinflammation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2021-06-14
Enrollment: 56
Sex: ALL
Minimum age (years): 15
Maximum age (years): 60
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Childhood and adult patients with C-ALD ; juvenile/adult patients with MLD; Adults patients with AMN ; Adults with leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) ; Healthy children without significant neurologic disease (15 months-18 years)

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Macrophages functionality - distribution of monocytes
timeFrame: 2 years after blood collection
measure: Macrophages functionality - myelin phagocytosis capacity
timeFrame: 2 years after blood collection
measure: Macrophages functionality - HLA levels
timeFrame: 2 years after blood collection
Secondary outcomes:
measure: Macrophages metabolic profiling
timeFrame: 2 years after blood collection
measure: Macrophages transcriptomic profiling
timeFrame: 2 years after blood collection
Other outcomes:
Locations:
city: Le Kremlin-Bicêtre
country: France
facility: AP-HP Hôpital Bicêtre
city: Paris
country: France
facility: AP-HP Hôpital La Pitié Salpêtrière
Study officials:
affiliation: Institut du Cerveau et de la Moëlle épinière
name: Fanny MOCHEL, MCU-PH
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut du Cerveau et de la Moëlle épinière
name: Violetta ZUJOVIC, PhD, CR1
role: STUDY_CHAIR
affiliation: Kremlin Bicêtre Hôpital
name: Caroline SEVIN, PhD
role: STUDY_DIRECTOR
References:
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.
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.
citation: 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.
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.