ClinicalTrials.gov
ClinicalTrials.gov Menu

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.
ClinicalTrials.gov Identifier: NCT01560182
Recruitment Status : Active, not recruiting
First Posted : March 22, 2012
Last Update Posted : December 19, 2018
Sponsor:
Collaborator:
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
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

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 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 : 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 (≥2 SD) increase of residual ARSA activity as compared to pre- treatment values, measured in PBMC and/or BM progenitors

  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 clinical (NCI ≥2) and laboratory (NCI ≥3) parameters 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: 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

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

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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 ClinicalTrials.gov identifier (NCT number): NCT01560182


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

Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Orchard Therapeutics
ClinicalTrials.gov 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: December 19, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Orchard Therapeutics:
OTL-200
Metachromatic Leukodystrophy
Gene Therapy
MLD
Previously GSK2696274

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
Sulfatidosis
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Leukoencephalopathies
Demyelinating Diseases
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lipidoses
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Lipid Metabolism Disorders