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Gene Therapy for Metachromatic Leukodystrophy (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 7, 2021
Ospedale San Raffaele
Information provided by (Responsible Party):
Orchard Therapeutics

Brief Summary:
This Phase I/II clinical trial consists of the application of lentiviral vector-based gene therapy to patients affected by Metachromatic Leukodystrophy (MLD), a rare inherited Lysosomal Storage Disorder (LSD) resulting from mutations in the gene encoding the Arylsulfatase A (ARSA) enzyme. The medicinal product consists of autologous CD34+ hematopoietic stem/progenitor cells in which a functional ARSA cDNA is introduced by means of 3rd generation VSV-G pseudotyped lentiviral vectors.

Condition or disease Intervention/treatment Phase
Lysosomal Storage Disease Metachromatic Leukodystrophy Genetic: OTL-200 Gene Therapy Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: N/A
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 : April 9, 2010
Actual Primary Completion Date : April 9, 2018
Estimated Study Completion Date : April 9, 2023

Arm Intervention/treatment
Experimental: OTL-200 Gene Therapy
CD34+ cells transduced ex vivo with lentiviral vector encoding ARSA cDNA
Genetic: OTL-200 Gene Therapy
Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA
Other Name: Previously GSK2696274

Primary Outcome Measures :
  1. 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 the GMFM scores in the historical control MLD population, evaluated 24 months after treatment.

  2. Increase of residual ARSA activity [ Time Frame: 24 months after treatment ]
    A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total PBMC

  3. Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]
    The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged aplasia), defined as Absolute Neutrophil Count (ANC)<500/µl

  4. Conditioning regimen-related toxicity [ Time Frame: 3 years ]
    The absence of regimen related toxicity, as determined by a surveillance of AEs (NCI ≥2) and laboratory parameters (NCI ≥3) that will be applied in the short- and long-term follow-up of the treated patients in order to assess the degree of morbidity associated to the conditioning regimen

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

  6. The long-term safety of lentiviral-transduced cell infusion [ Time Frame: baseline and after 1, 3, 6, 12 and 24 months ]
    Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen

Secondary Outcome Measures :
  1. The absence of immune responses against the transgene (immunoblot analyses). [ Time Frame: every three months for the first year, then once a year. ]
    Even if an immune responses against the functional ARSA enzyme is not expected, treated subjects will be monitored for antibodies anti-ARSA on a defined schedule.

  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 brain MRI score.

  3. Transduced cell engraftment [ Time Frame: 12 months after treatment ]
    Transduced cell engraftment above 4% in bone marrow-derived clonogenic progenitor cells. Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and BM cell subpopulations will also be evaluated.

  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 testings

Information from the National Library of Medicine

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Ages Eligible for Study:   up to 7 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Pre-symptomatic MLD patients with the late infantile variant;
  • Pre- or early-symptomatic MLD patients with the early juvenile variant;
  • Patients for whom parental/guardian signed informed consent has been obtained.

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

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Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Milan, Italy, 20132
Sponsors and Collaborators
Orchard Therapeutics
Ospedale San Raffaele
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Study Director: Orchard Clinical Trials Orchard Therapeutics

Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Orchard Therapeutics Identifier: NCT01560182    
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 7, 2021
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Orchard Therapeutics:
Metachromatic Leukodystrophy
Gene Therapy
Previously GSK2696274
Additional relevant MeSH terms:
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Leukodystrophy, Metachromatic
Lysosomal Storage Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic 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
Lipid Metabolism, Inborn Errors
Lipid Metabolism Disorders