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NCT Number: NCT01801709

Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy

The objective of this open-label, single arm, monocentric, phase I/II clinical study is to assess safety and efficacy of ARSA gene transfer in the brain of children affected with early onset forms of Metachromatic Leukodystrophy (MLD). For this purpose, an adeno-associated virus serotype rh.10 (AAVrh.10) vector will be used to transfer the ARSA cDNA coding for Arylsulfatase A (ARSA) enzyme into the brain of children. Five patients with early onset form of MLD, age ranging from 6 months to 4 years, will be included in this protocol and will be followed during 24 months.

Patients will be selected at presymptomatic or early stage of their disease, following clinical, neuropsychological and brain imaging criteria.

Twelve simultaneous injections of the investigational medicinal product will be performed in the white matter of both brain hemispheres, through 6 image-guided tracks, with 2 deposits per track.

A low dose (1x10EXP12 vg total) will be administered to the first 2 patients, while the last 3 will receive a higher dose (4x10EXP12 vg total).

Safety and efficiency will be evaluated based on clinical, neuropsychological, radiological, electrophysiological and biological parameters.

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Key information

Conditions

Metachromatic Leukodystrophy Brain Diseases Brain Diseases, Metabolic Brain Diseases, Metabolic, Inborn Central Nervous System Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Demyelinating Diseases Genetic Diseases, Inborn Hereditary Central Nervous System Demyelinating Diseases Leukodystrophy, Metachromatic Leukoencephalopathies Lipid Metabolism Disorders Lipid Metabolism, Inborn Errors Lipidoses Lysosomal Storage Diseases Lysosomal Storage Diseases, Nervous System Metabolic Diseases Metabolism, Inborn Errors Nervous System Diseases Nutritional and Metabolic Diseases Sphingolipidoses Sulfatidosis

Age range

6 month–5 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Bicêtre Hospital - Paris Sud

Le Kremlin-Bicêtre, France

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Boys or girls with an early onset form of MLD.
  • Age between 6 months and 5 years, inclusive
  • Diagnostic of MLD based on the measurement of ARSA activity in leukocytes and the accumulation of sulfatides in urine, along with normal activity of at least one other sulfatase
  • Informed consent signed up and willingness for monitoring 2 years after treatment.
  • Normal values for standard laboratory tests

Exclusion criteria

  • Absence of ARSA protein by immunocytochemistry and/or ELISA
  • Gestational age <32 weeks of amenorrhoea and age < 1 year
  • Brain atrophy with a subdural space > 10 mm in the frontal region
  • Performance IQ<50 at WPPSI-III or cognitive function < 3rd percentile at the Bayley's test of infant development
  • If age > 16 months at inclusion, inability to walk few steps alone OR inability to walk few steps with support on one side along with inability to stand up alone
  • Impossibility for anesthesia
  • Malignancy, cardiac malformation, liver dysfunction, or renal dysfunction
  • Neurological disorder, except benign, not related to MLD.
  • Any other clinically significant untreated co-morbid medical condition as determined by the clinical investigator, including cardiac, pulmonary or kidney disease.
  • MRI impossibility
  • Evoked potential impossibility
  • Participation to another therapeutic clinical trial for MLD.
  • Unaffiliated to any French or any other National Health Insurance.

Treatment and study plan

intracerebral administration of AAVrh.10cuARSA

Genetic

Primary outcomes

  1. Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA

    Time frame: During the two years follow-up

    Tolerance will be measured by :

    • Adverse event,
    • Clinical and neurological exams,
    • Laboratory tests,
    • Neuroimagery (CT scan, brain MRI).

Secondary outcomes

  1. Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression.

    Time frame: During the two years follow-up

    Efficacy will be measured by:

    • MLD neurological severity score,
    • Neurological evaluation,
    • Motor scores (GMFM, Ashworth and ICARS),
    • Cognitive functions (Bayley Scales of Infant Development (BSID)(0-42 months), or Wechsler Preschool and Primary Scale of Intelligence-III (WPPSI-III) (43 months-6 years)),
    • MLD severity MRI score, MRI-DTI parameters, measurement of cerebral atrophy and spectroscopy,
    • Neuroelectrophysiological tests (peripheral nerve conduction velocity, visual, auditory and somatosensory evoked potentials).

Sponsors and collaborators

Lead sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Other Gov

Collaborators

  • Assistance Publique - Hôpitaux de Paris
  • European Leukodystrophy Association

Registry information

Official study title

A Phase I/II, Open Labeled, Monocentric Study of Direct Intracranial Administration of a Replication Deficient Adeno-associated Virus Gene Transfer Vector Serotype rh.10 Expressing the Human ARSA cDNA to Children With Metachromatic Leukodystrophy.

Acronym: TG-MLD

Important dates

Study start
2014
Primary completion
2016
Study completion
2022
First posted
Mar 1, 2013
Registry last updated
Mar 2, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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