Intracerebral Gene Therapy for Children With Early Onset Forms of Metachromatic Leukodystrophy (TG-MLD)

January 10, 2022 updated by: Institut National de la Santé Et de la Recherche Médicale, France

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.

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Anticipated)

5

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Le Kremlin-Bicêtre, France
        • Bicêtre Hospital - Paris Sud

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 months to 5 years (Child)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: AAVrh.10cuARSA
intracerebral administration of AAVrh.10cuARSA at 12 sites in the white matter of both brain hemispheres.
Genetic: intracerebral administration of AAVrh.10cuARSA

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
During the two years follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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).
During the two years follow-up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

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

Collaborators

Assistance Publique - Hôpitaux de Paris
European Leukodystrophy Association

Investigators

  • 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 and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 1, 2014

Primary Completion (Actual)

June 1, 2016

Study Completion (Anticipated)

May 1, 2029

Study Registration Dates

First Submitted

January 28, 2013

First Submitted That Met QC Criteria

February 27, 2013

First Posted (Estimate)

March 1, 2013

Study Record Updates

Last Update Posted (Actual)

January 11, 2022

Last Update Submitted That Met QC Criteria

January 10, 2022

Last Verified

January 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • C11-09
  • 2011-004410-42 (EudraCT Number)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Metachromatic Leukodystrophy

Clinical Trials on intracerebral administration of AAVrh.10cuARSA

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Ecuador

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe