Clinical Trial: Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

Official Title: A Phase I/II Clinical Trial of Lentiviral Hematopoietic Stem Cell Gene Therapy for Treatment of Developed Metachromatic Leukodystrophy and Adrenoleukodystrophy

Brief Summary: Evaluating the safety and efficacy of Lentiviral Hematopoietic Stem Cell Gene Therapy for advanced stage of Metachromatic Leukodystrophy and adrenoleukodystrophy.

Detailed Summary:

This is a phase I/II protocol aiming at the assessment of the safety and efficacy of arylsulfatase A（ARSA) / adenosine-triphosphate-binding cassette, sub-family D (ABCD1) gene transfer into hematopoietic stem/progenitor cells for the treatment of metachromatic leukodystrophy/adrenoleukodystrophy.

Metachromatic Leukodystrophy (MLD) is an autosomal recessive Lysosomal Storage Disorder (LSD) characterized by severe and progressive dysmyelination affecting the central and peripheral nervous system. Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, ALD, X-ALD), a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very-long chain fatty acids (VLCFA) in tissues throughout the body, is caused by mutations in ABCD1.Both diseases are characterized by progressive neurodegenerative decline, leading to a devastating state without treatment.

Hematopoietic cell transplantation (HCT) is ineffective in ameliorating patients' phenotype or delaying disease evolution in many patients. 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/ALD patients.

Recently, an Italian group conducted 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 (ClinicalTrials.gov Identifier:

NCT01560182).The safety and efficacy of this gene therapy approach in MLD patients was evaluated.During 3 years of follow-up, they reported multilineage ARSA expression and ability to prevent and correct neurologic
Sponsor: Shenzhen Second People's Hospital

Current Primary Outcome:

  • The short-term safety and tolerability after hematopoietic stem cell transplanation [ Time Frame: 2 months ]
    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 recovery, requiring cellular back-up administration.
  • Incidence of Treatment-Emergent Adverse Events(For MLD) [ Time Frame: 72 hours ]
    It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
  • Incidence of Treatment-Emergent Adverse Events(For ALD) [ Time Frame: 72 hours ]
    It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
  • Neurologic deficit [ Time Frame: up to 5 years ]
    Before and after transplanation 1/2 year, 1 year, 3 years,and 5 years,Neurologic deficit will be scored according to previous publication from Peters et al. (2004) Blood 104(3):881-888 for patients
  • Neuropsychological testing [ Time Frame: up to 5 years ]
    Before and after transplanation 1/2 year , 1 year, 3 years,and 5 years, the patients will be subjected to neuropsychologic testing by using age-matched Wechsler Intelligence Scale for Children(WISC-III score )system between 6-16 years. above 16 -90 years, pati

    Original Primary Outcome: Same as current

    Current Secondary Outcome:

    • immune responses against the transgene(For MLD) [ Time Frame: 5 years ]
      Before and after transplantation 1/2 year , 1 year, 3 years and 5 years ,treated patients will be monitored if generation of ARSA antiboy (MLD) by immunoblot analyses.
    • immune responses against the transgene(For ALD) [ Time Frame: 5 years ]
      Before and after transplantation 1/2 year , 1 year, 3 years and 5 years ,treated patients will be monitored if generation of or ABCD1 antibody by immunoblot analyses.


    Original Secondary Outcome: Same as current

    Information By: Shenzhen Second People's Hospital

    Dates:
    Date Received: August 12, 2015
    Date Started: January 2015
    Date Completion: October 2025
    Last Updated: September 23, 2015
    Last Verified: September 2015