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

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.

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.

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.