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

NCT01801709 | Completed Phase 1 DMC

• 2 other identifiers: C11-092011-004410-42
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

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

Keywords

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

Outcome Measures

Primary Outcomes (1)

• 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).

  During the two years follow-up

Secondary Outcomes (1)

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

  During the two years follow-up

Study Arms (1)

AAVrh.10cuARSA

EXPERIMENTAL

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

Genetic: intracerebral administration of AAVrh.10cuARSA

Interventions

intracerebral administration of AAVrh.10cuARSA GENETIC

AAVrh.10cuARSA

Eligibility Criteria

• Age: 6 Months - 5 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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.

Sponsors & Collaborators

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

Study Sites (1)

Bicêtre Hospital - Paris Sud

Le Kremlin-Bicêtre, France

Location

Related Publications (5)

• 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.

  PMID: 22642214 BACKGROUND

• 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.

  PMID: 23131032 BACKGROUND

• 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.

  PMID: 19837699 BACKGROUND

• 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.

  PMID: 21098404 BACKGROUND

• 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.

  PMID: 25758611 RESULT

MeSH Terms

Conditions

Leukodystrophy, Metachromatic

Condition Hierarchy (Ancestors)

Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Study Officials

• Patrick Aubourg, MD-PhD

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

  PRINCIPAL INVESTIGATOR

• 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

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2013
• First Posted: March 1, 2013
• Study Start: June 1, 2014
• Primary Completion: June 1, 2016
• Study Completion: December 20, 2022
• Last Updated: March 2, 2026

Record last verified: 2025-01

Locations

FR (1)