Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy (TG-MLD)
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|ClinicalTrials.gov Identifier: NCT01801709|
Recruitment Status : Active, not recruiting
First Posted : March 1, 2013
Last Update Posted : January 11, 2022
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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 Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||5 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|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 :||June 2014|
|Actual Primary Completion Date :||June 2016|
|Estimated Study Completion Date :||May 2029|
intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.
Genetic: intracerebral administration of AAVrh.10cuARSA
- Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA [ Time Frame: During the two years follow-up ]
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 ]
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).
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|Ages Eligible for Study:||6 Months to 5 Years (Child)|
|Sexes Eligible for Study:||All|
|Accepts Healthy Volunteers:||No|
- 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
- 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01801709
|Bicêtre Hospital - Paris Sud|
|Le Kremlin-Bicêtre, France|
|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|
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
|Responsible Party:||Institut National de la Santé Et de la Recherche Médicale, France|
|Other Study ID Numbers:||
2011-004410-42 ( EudraCT Number )
|First Posted:||March 1, 2013 Key Record Dates|
|Last Update Posted:||January 11, 2022|
|Last Verified:||January 2022|
Brain Gene Therapy
Adeno Associated vector
Lysosomal sotage diseases
Hereditary Central Nervous System Demyelinating Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Central Nervous System Diseases
Nervous System Diseases
Lysosomal Storage Diseases, Nervous System
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Lipid Metabolism Disorders