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NCT Number: NCT01560182

Gene Therapy for Metachromatic Leukodystrophy (MLD)

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.

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Key information

Conditions

Lysosomal Storage Disease Brain Diseases Brain Diseases, Metabolic Brain Diseases, Metabolic, Inborn Central Nervous System Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Demyelinating Diseases Genetic Diseases, Inborn Hereditary Central Nervous System Demyelinating Diseases Leukodystrophy, Metachromatic Leukoencephalopathies Lipid Metabolism Disorders Lipid Metabolism, Inborn Errors Lipidoses Lysosomal Storage Diseases Lysosomal Storage Diseases, Nervous System Metabolic Diseases Metabolism, Inborn Errors Metachromatic Leukodystrophy Nervous System Diseases Nutritional and Metabolic Diseases Sphingolipidoses Sulfatidosis

Age range

Up to 7 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Milan, 20132, Italy

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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/other therapeutic approaches that might become available;
  • 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.

Treatment and study plan

OTL-200 Gene Therapy

Genetic

Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA

Other names: Previously GSK2696274

Primary outcomes

  1. Improvement of Gross Motor Function Measure (GMFM) score

    Time frame: 24 months after treatment

    An improvement of 10% of the total GMFM score in treated patients, when compared to the GMFM scores in the historical control MLD population, evaluated 24 months after treatment.

  2. Increase of residual Arylsulfatase A (ARSA) activity

    Time frame: 24 months after treatment

    A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total Peripheral Blood Mononuclear Cells (PBMCs)

  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, with no evidence of Bone Marrow (BM) recovery, requiring cellular back-up administration.

  4. Conditioning regimen-related toxicity

    Time frame: 3 years after treatment

    The absence of regimen related toxicity, as determined by a surveillance of adverse events (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 treatment infusion

    It will be evaluated on the basis of AEs reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash). Evaluation will also consist of the absence of Serious Adverse Reactions (SARs) within 48 hours after infusion.

  6. The long-term safety of lentiviral-transduced cell infusion

    Time frame: baseline, 1, 3, 6, and 12 months after treatment, then once a year

    Absence of Replication Competent Lentivirus: Assessed via enzyme-linked immunosorbent assay (ELISA) test for serum human immunodeficiency virus (HIV) p24 antigen. Positive HIV p24 test result is subject to second level testing including: a) DNA PCR for vesicular stomatitis virus G (VSV-G) envelope (PBMC) and b) reverse transcription (RT) PCR for HIV-pol ribonucleic acid (RNA) (plasma).

  7. The long-term safety of lentiviral-transduced cell infusion

    Time frame: baseline, 3, 6 and 12 months after treatment, then once a year

    Absence of Abnormal Clonal Proliferation: monitored by clinical and laboratory surveillance, TCR Vβ repertoire analysis, and bone marrow examination.

  8. The long-term safety of lentiviral-transduced cell infusion

    Time frame: 6 and 12 months after treatment, then once a year

    Lentiviral vector integration site analysis will also be performed

Secondary outcomes

  1. The absence of immune responses against the transgene (immunoblot analyses).

    Time frame: baseline, 3, 6, and 12 months after treatment, then once a year

    Even if immune responses against the functional ARSA enzyme are not expected, treated subjects will be monitored for anti-ARSA antibodies on a defined schedule.

  2. Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score.

    Time frame: 24 months after treatment

    The NCV Index and the total brain MRI score will be compared to scores observed in the historical control MLD population.

    Gross Motor Function Classification for MLD (GMFC-MLD) levels at different ages compared to the historical control MLD population.

  3. Transduced cell engraftment

    Time frame: 12 months after treatment

    Transduced cell engraftment above 4% in bone marrow-derived clonogenic progenitor cells, assessed as the percentage of LV-positive colonies. Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and bone marrow (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 cognitive impairment) at neuro-psychological testings

Sponsors and collaborators

Lead sponsor

Orchard Therapeutics

Industry

Collaborators

  • Ospedale San Raffaele

Registry information

Official study title

A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy

Important dates

Study start
2010
Primary completion
2018
Study completion
2025
First posted
Mar 22, 2012
Registry last updated
Dec 5, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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