Clinical trial NCT01801709: Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy
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
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metachromatic Leukodystrophy
Keywords: Brain Gene Therapy
Adeno Associated vector
Lysosomal sotage diseases
Leukodystrophies
Lead sponsor: Institut National de la Santé Et de la Recherche Médicale, France
Sponsor class: OTHER_GOV
Collaborators: name: European Leukodystrophy Association
name: Assistance Publique - Hôpitaux de Paris
First posted: 2013-03-01
Enrollment: 5
Sex: ALL
Minimum age (years): 6
Maximum age (years): 5
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Evaluate the tolerance of the intracerebral administration of a single dose of AAVrh.10cuARSA
timeFrame: During the two years follow-up
Secondary outcomes:
measure: Evaluate the efficacy of intracerebral administration of a single dose of AAVrh.10cuARSA to stop the disease progression.
timeFrame: During the two years follow-up
Other outcomes:
Locations:
city: Le Kremlin-Bicêtre
country: France
facility: Bicêtre Hospital - Paris Sud
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale
name: Patrick Aubourg, MD-PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Caroline Sevin, MD-PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Michel Zerah, MD, PhD
role: STUDY_DIRECTOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Thomas Roujeau, MD, PhD
role: STUDY_DIRECTOR
affiliation: Institut National de la Santé et de la Recherche Biomédicale
name: Nathalie Cartier, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.