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

Primary Purpose

Metachromatic Leukodystrophy

Status

Active

Phase

Phase 1

Locations

France

Study Type

Interventional

Intervention

intracerebral administration of AAVrh.10cuARSA

About this trial

This is an interventional treatment trial for Metachromatic Leukodystrophy focused on measuring Brain Gene Therapy, Adeno Associated vector, Lysosomal sotage diseases, Leukodystrophies

Eligibility Criteria

6 Months - 5 Years (Child)All SexesDoes not accept 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.

Sites / Locations

Bicêtre Hospital - Paris Sud

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AAVrh.10cuARSA

Arm Description

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

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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).

Full Information

NCT ID

NCT01801709

First Posted

January 28, 2013

Last Updated

January 10, 2022

Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Collaborators

European Leukodystrophy Association, Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT01801709

Brief Title

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

Acronym

TG-MLD

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.

Study Type

Interventional

2. Study Status

Record Verification Date

January 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

June 2014 (Actual)

Primary Completion Date

June 2016 (Actual)

Study Completion Date

May 2029 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut National de la Santé Et de la Recherche Médicale, France

Collaborators

European Leukodystrophy Association, Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee

Yes

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metachromatic Leukodystrophy

Keywords

Brain Gene Therapy, Adeno Associated vector, Lysosomal sotage diseases, Leukodystrophies

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

5 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

AAVrh.10cuARSA

Arm Type

Experimental

Arm Description

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

Intervention Type

Genetic

Intervention Name(s)

intracerebral administration of AAVrh.10cuARSA

Primary Outcome Measure Information:

Title

Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA

Description

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 Outcome Measure Information:

Title

Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression.

Description

Time Frame

During the two years follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Months

Maximum Age & Unit of Time

5 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials: