TG-MLD: Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01801709

Collaborator

European Leukodystrophy Association (Other), Assistance Publique - Hôpitaux de Paris (Other)

Enrollment

Location

Arm

179

Anticipated Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metachromatic Leukodystrophy	Genetic: intracerebral administration of AAVrh.10cuARSA	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

5 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (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.

Actual Study Start Date :

Jun 1, 2014

Actual Primary Completion Date :

Jun 1, 2016

Anticipated Study Completion Date :

May 1, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AAVrh.10cuARSA intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.	Genetic: intracerebral administration of AAVrh.10cuARSA

Arm

Intervention/Treatment

Experimental: AAVrh.10cuARSA

intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.

Genetic: intracerebral administration of AAVrh.10cuARSA

Outcome Measures

Primary Outcome Measures

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

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).

Eligibility Criteria

Criteria

Ages Eligible for Study:

6 Months to 5 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bicêtre Hospital - Paris Sud	Le Kremlin-Bicêtre		France

Sponsors and Collaborators

Institut National de la Santé Et de la Recherche Médicale, France
European Leukodystrophy Association
Assistance Publique - Hôpitaux de Paris

Investigators

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