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

Institut National de la Santé Et de la Recherche Médicale, France5 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metachromatic Leukodystrophy

Interventions

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 5 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

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).

Time frame: During the two years follow-up

Secondary Outcomes

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).