Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy (TG-MLD)
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.
Genetic: intracerebral administration of AAVrh.10cuARSA
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official 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.|
- Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA [ Time Frame: During the two years follow-up ] [ Designated as safety issue: Yes ]
Tolerance will be measured by :
- Adverse event,
- Clinical and neurological exams,
- Laboratory tests,
- Neuroimagery (CT scan, brain MRI).
- 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 ] [ Designated as safety issue: No ]
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).
|Study Start Date:||March 2013|
|Estimated Study Completion Date:||April 2018|
|Estimated Primary Completion Date:||March 2018 (Final data collection date for primary outcome measure)|
intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.
|Genetic: intracerebral administration of AAVrh.10cuARSA|
|Contact: Patrick Aubourg, MD - PhD||33.1 4959 firstname.lastname@example.org|
|Contact: Caroline Sevin, MD - PhD||33.1 4521 email@example.com|
|Bicêtre Hospital - Paris Sud||Recruiting|
|Le Kremlin-Bicêtre, France|
|Contact: Patrick Aubourg firstname.lastname@example.org|
|Contact: Caroline Sevin email@example.com|
|Principal Investigator: Patrick Aubourg|
|Principal Investigator: Caroline Sevin|
|Principal Investigator:||Patrick Aubourg, MD-PhD||Assistance Publique - Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale|
|Study Director:||Caroline Sevin, MD-PhD||Assistance Publique - Hôpitaux de Paris|
|Study Director:||Michel Zerah, MD, PhD||Assistance Publique - Hôpitaux de Paris|
|Study Director:||Thomas Roujeau, MD, PhD||Assistance Publique - Hôpitaux de Paris|
|Study Director:||Nathalie Cartier, MD, PhD||Institut National de la Santé et de la Recherche Biomédicale|