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

Study Overview
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Brief Summary
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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.

Official Title
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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.

Conditions
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Metachromatic Leukodystrophy

Intervention / Treatment
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* Genetic: intracerebral administration of AAVrh.10cuARSA


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AAVrh.10cuARSA<br>intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres. | Genetic: intracerebral administration of AAVrh.10cuARSA<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA | Tolerance will be measured by : Adverse event, Clinical and neurological exams, Laboratory tests, Neuroimagery (CT scan, brain MRI). | During the two years follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression. | 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). | During the two years follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Gene Therapy, Adeno Associated vector, Lysosomal sotage diseases, Leukodystrophies