Gene Therapy for Metachromatic Leukodystrophy (TIGET-MLD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01560182
Recruitment Status : Active, not recruiting
First Posted : March 22, 2012
Last Update Posted : October 15, 2018
Fondazione Telethon
Information provided by (Responsible Party):

Brief Summary:
This is a phase I/II protocol aiming at the assessment of the safety and efficacy of ARSA gene transfer into hematopoietic stem/progenitor cells for the treatment of Metachromatic Leukodystrophy.

Condition or disease Intervention/treatment Phase
Lysosomal Storage Disease Genetic: Autologous CD34+ stem cells transduced with ARSA encoding lentiviral vector Phase 2

Detailed Description:

Metachromatic Leukodystrophy (MLD) is an autosomal recessive Lysosomal Storage Disorder (LSD) characterized by severe and progressive dysmyelination affecting the central and peripheral nervous system.

Hematopoietic cell transplantation (HCT) is ineffective in ameliorating patients' phenotype or delaying disease evolution. No evidences of efficacy of enzyme replacement strategies are available at the moment. Transplantation of genetically corrected autologous hematopoietic stem cells (HSC) could represent a novel and potentially efficacious treatment for MLD patients.

We are conducting a gene therapy clinical trial based on autologous HSC and advanced generation lentiviral vectors (LV) for patients affected by the most severe, early onset forms of the disease, based on our preclinical efficacy and safety data and on the experience we acquired from the treatment of Adenosine deaminase deficiency (ADA-SCID) patients by a similar approach. Our general goal is to demonstrate safety and efficacy of this gene therapy approach in MLD patients. We have developed and tested a clinically applicable LV containing the ARSA cDNA controlled by a constitutive eukaryotic promoter sequence. Preclinical studies aimed at assessing efficacy and safety of ARSA gene transfer using the selected vector have been conducted in the murine model of the disease and in progenitors and mature hematopoietic cells from MLD patients. The following results were obtained:

  1. efficient ARSA gene transfer;
  2. long term in vitro and in vivo multilineage ARSA expression;
  3. ability to prevent and correct neurological disease manifestations;
  4. good tolerance and long-term safety of the treatment in the animal model.

We expect to treat 20 patients, selected according to disease severity and clinical features. A myeloablative conditioning regimen based on iv Busulfan will be administered to the patients to enable engraftment of the transduced stem/progenitor cells in the bone marrow and enhance CNS microglia/macrophage repopulation by the transduced cell progeny. An efficient transduction protocol based on LVs has been optimized to guarantee abundant ARSA expression in the transduced patients' HSC and their progeny. In the treated patients, we will study the short-term and long-term safety of the administration of the autologous transduced HSC, their long-term engraftment, the expression of vector-derived ARSA, and the ability of the transduced cells to provide a clinical benefit to the patients. The treated patients will be followed for 3 years and thereafter monitored for the safety of gene therapy for additional 5 years. If successful, this study will provide key results on the safety and efficacy of gene therapy for MLD patients.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy
Actual Study Start Date : May 7, 2010
Estimated Primary Completion Date : April 13, 2023
Estimated Study Completion Date : April 18, 2023

Intervention Details:
  • Genetic: Autologous CD34+ stem cells transduced with ARSA encoding lentiviral vector
    Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA under the control of the human phosphoglyceratekinase (PGK) promoter. Dose: ≥ 2x10^6 transduced CD34+ cells/Kg (maximum 20x10^6) at bedside for infusion.

Primary Outcome Measures :
  1. Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]
    The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged

  2. Conditioning regimen-related toxicity [ Time Frame: 3 years ]
    The absence of regimen related toxicity, as determined by a surveillance of clinical (NCI >2

  3. The short-term safety and tolerability of lentiviral-transduced cell infusion [ Time Frame: 48 hours after transplant ]
    It will be evaluated on the basis of adverse events reporting and monitoring of the systemic

  4. Improvement of GMFM score [ Time Frame: 24 months after treatment ]
    An improvement of 10% of the total GMFM score in treated patients, when compared to the

  5. Increase of residual ARSA activity [ Time Frame: 24 months after treatment ]
    A significant (≥ 2 SD) increase of residual ARSA activity as compared to pretreatment

  6. The long-term safety of lentiviral-transduced cell infusion [ Time Frame: 24 months after the treatment ]
    Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen

Secondary Outcome Measures :
  1. The absence of immune responses against the transgene [ Time Frame: every three months for the first year, then once a year. ]
    Even if we do not expect immune responses against the functional ARSA enzyme,

  2. Improvement in the NCV Index for ENG and in the total score for MR [ Time Frame: 24 months after treatment ]
    An improvement in the NCV Index for ENG and in the total score for MR of ≥ 2 SD, when

  3. Transduced cell engraftment [ Time Frame: 12 months after treatment ]
    Transduced cell engraftment above 4% in PBMCs and CD34+ progenitors in BM

  4. IQ measurement above 55 [ Time Frame: 24, 30 and 36 months after treatment ]
    The measurement of an IQ above 55 (threshold for severe disability) at neuro-psychological

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Pre-symptomatic late infantile patients
  • Pre- or early-symptomatic early juvenile patients (IQ > 70 and ability to walk independently for >10 steps)
  • Parental/guardian/patient signed informed consent.

Exclusion Criteria:

  • HIV RNA and/or HCV RNA and/or HBV DNA positive patients
  • Patients affected by neoplastic diseases
  • Patients with cytogenetic alterations typical of MDS/AML
  • Patients with end-organ functions or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study
  • Patients enrolled in other trials.
  • Patient who underwent allogeneic hematopoietic stem cell transplantation in the previous six months.
  • Patient who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01560182

GSK Investigational Site
Milan, Italy, 20132
Sponsors and Collaborators
Fondazione Telethon
Study Director: GSK Clinical Trials GlaxoSmithKline


Publications automatically indexed to this study by Identifier (NCT Number):
Responsible Party: GlaxoSmithKline Identifier: NCT01560182     History of Changes
Other Study ID Numbers: 201222
Eudract 2009-017349-77 ( Other Identifier: IRCCS San Raffaele )
First Posted: March 22, 2012    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 2018

Keywords provided by GlaxoSmithKline:
Lentiviral vector
Metachromatic Leukodystrophy
Gene Therapy

Additional relevant MeSH terms:
Leukodystrophy, Metachromatic
Lysosomal Storage Diseases
Hereditary Central Nervous System Demyelinating Diseases
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lysosomal Storage Diseases, Nervous System
Demyelinating Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Lipid Metabolism Disorders