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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
Sponsored by
Institut National de la Santé Et de la Recherche Médicale, France
About
Eligibility
Locations
Arms
Outcomes
Full info

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

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
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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
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).
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
No
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:
First Name & Middle Initial & Last Name & Degree
Patrick Aubourg, MD-PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris and Institut National de la Santé et de la Recherche Médicale
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Caroline Sevin, MD-PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Michel Zerah, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Thomas Roujeau, MD, PhD
Organizational Affiliation
Assistance Publique - Hôpitaux de Paris
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Nathalie Cartier, MD, PhD
Organizational Affiliation
Institut National de la Santé et de la Recherche Biomédicale
Official's Role
Study Director
Facility Information:
Facility Name
Bicêtre Hospital - Paris Sud
City
Le Kremlin-Bicêtre
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
22642214
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.
Results Reference
background
PubMed Identifier
23131032
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.
Results Reference
background
PubMed Identifier
19837699
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.
Results Reference
background
PubMed Identifier
21098404
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.
Results Reference
background
PubMed Identifier
25758611
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.
Results Reference
derived

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

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