Intracerebral Gene Therapy for Children with Early Onset Forms of Metachromatic Leukodystrophy
- Conditions
- Metachromatic Leukodystrophy
- Interventions
- Genetic: intracerebral administration of AAVrh.10cuARSA
- Registration Number
- NCT01801709
- Lead Sponsor
- Institut National de la Santé Et de la Recherche Médicale, France
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 5
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description AAVrh.10cuARSA intracerebral administration of AAVrh.10cuARSA intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.
- Primary Outcome Measures
Name Time Method Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA 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 Outcome Measures
Name Time Method Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression. 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).
Trial Locations
- Locations (1)
Bicêtre Hospital - Paris Sud
🇫🇷Le Kremlin-Bicêtre, France