Modeling Macrophages Activation Pattern in X-linked Adrenoleukodystrophy and Metachromatic Leukodystrophy

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Brief Title

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"

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.
    


Study Type

Observational


Primary Outcome

Macrophages functionality - distribution of monocytes

Secondary Outcome

 Macrophages metabolic profiling

Condition

Adrenoleukodystrophy

Intervention

Blood sample collection

Study Arms / Comparison Groups

 affected subjects
Description:  adult patients with adrenomyeloneuropathy/adrenoleukodystrophy
children with adrenoleukodystrophy
children with metachromatic leukodystrophy

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

49

Start Date

August 30, 2021

Completion Date

December 2023

Primary Completion Date

June 2023

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)

          -  Adult males or females diagnosed with MLD (low ARSA activity and accumulation of
             sulfatides in urine)

          -  Adult males diagnosed with AMN (elevated VLCFA and clinical symptoms of AMN without
             leukodystrophy at brain MRI)

          -  Adult male diagnosed with CALD (elevated VLCFA with leukodystrophy at brain MRI)

          -  Adult male or female diagnosed with ALSP (genetic confirmation with 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
      

Gender

All

Ages

15 Months - 60 Years

Accepts Healthy Volunteers

Accepts Healthy Volunteers

Contacts

Fanny MOCHEL, MCU-PH, 01 57 27 44 82, [email protected]

Location Countries

France

Location Countries

France

Administrative Informations


NCT ID

NCT04925349

Organization ID

APHP190197


Responsible Party

Sponsor

Study Sponsor

Assistance Publique - Hôpitaux de Paris


Study Sponsor

Fanny MOCHEL, MCU-PH, Principal Investigator, Institut du Cerveau et de la Moëlle épinière


Verification Date

April 2022