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

NCT ID: NCT01801709

Last Updated: 2025-11-18

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 5 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-06-30
• Study Completion Date: 2022-12-20

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.

Conditions

Metachromatic Leukodystrophy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

AAVrh.10cuARSA

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

Group Type: EXPERIMENTAL

intracerebral administration of AAVrh.10cuARSA

Intervention Type: GENETIC

Interventions

intracerebral administration of AAVrh.10cuARSA

Intervention Type: GENETIC

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.

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 5 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

European Leukodystrophy Association

OTHER

Sponsor Role: collaborator

Assistance Publique - Hôpitaux de Paris

OTHER

Sponsor Role: collaborator

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

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Patrick Aubourg, MD-PhD

Role: PRINCIPAL_INVESTIGATOR

Assistance Publique - Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale

Caroline Sevin, MD-PhD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Michel Zerah, MD, PhD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Thomas Roujeau, MD, PhD

Role: STUDY_DIRECTOR

Assistance Publique - Hôpitaux de Paris

Nathalie Cartier, MD, PhD

Role: STUDY_DIRECTOR

Institut National de la Santé et de la Recherche Biomédicale

Locations

Bicêtre Hospital - Paris Sud

Le Kremlin-Bicêtre, , France

Countries

France

References

Piguet F, Sondhi D, Piraud M, Fouquet F, Hackett NR, Ahouansou O, Vanier MT, Bieche I, Aubourg P, Crystal RG, Cartier N, Sevin C. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum Gene Ther. 2012 Aug;23(8):903-14. doi: 10.1089/hum.2012.015. Epub 2012 Jul 23.

Reference Type: BACKGROUND

PMID: 22642214 (View on PubMed)

Sondhi D, Johnson L, Purpura K, Monette S, Souweidane MM, Kaplitt MG, Kosofsky B, Yohay K, Ballon D, Dyke J, Kaminksy SM, Hackett NR, Crystal RG. Long-term expression and safety of administration of AAVrh.10hCLN2 to the brain of rats and nonhuman primates for the treatment of late infantile neuronal ceroid lipofuscinosis. Hum Gene Ther Methods. 2012 Oct;23(5):324-35. doi: 10.1089/hgtb.2012.120. Epub 2012 Nov 6.

Reference Type: BACKGROUND

PMID: 23131032 (View on PubMed)

Colle MA, Piguet F, Bertrand L, Raoul S, Bieche I, Dubreil L, Sloothaak D, Bouquet C, Moullier P, Aubourg P, Cherel Y, Cartier N, Sevin C. Efficient intracerebral delivery of AAV5 vector encoding human ARSA in non-human primate. Hum Mol Genet. 2010 Jan 1;19(1):147-58. doi: 10.1093/hmg/ddp475.

Reference Type: BACKGROUND

PMID: 19837699 (View on PubMed)

i Dali C, Hanson LG, Barton NW, Fogh J, Nair N, Lund AM. Brain N-acetylaspartate levels correlate with motor function in metachromatic leukodystrophy. Neurology. 2010 Nov 23;75(21):1896-903. doi: 10.1212/WNL.0b013e3181feb217.

Reference Type: BACKGROUND

PMID: 21098404 (View on PubMed)

Zerah M, Piguet F, Colle MA, Raoul S, Deschamps JY, Deniaud J, Gautier B, Toulgoat F, Bieche I, Laurendeau I, Sondhi D, Souweidane MM, Cartier-Lacave N, Moullier P, Crystal RG, Roujeau T, Sevin C, Aubourg P. Intracerebral Gene Therapy Using AAVrh.10-hARSA Recombinant Vector to Treat Patients with Early-Onset Forms of Metachromatic Leukodystrophy: Preclinical Feasibility and Safety Assessments in Nonhuman Primates. Hum Gene Ther Clin Dev. 2015 Jun;26(2):113-24. doi: 10.1089/humc.2014.139. Epub 2015 Apr 28.

Reference Type: RESULT

PMID: 25758611 (View on PubMed)

Other Identifiers

2011-004410-42

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

C11-09

Identifier Type: -

Identifier Source: org_study_id