Brief Title
Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
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 Description
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 neurological disease manifestations.However, only pre-symptomatic late
infantile/Pre- or early-symptomatic early juvenile patients were recruited into the trial. In
most cases, MLD/ALD patients tend to be diagnosed at an advanced stage, missing the best
timing of curable HSC intervention. In our study, we intend to recruit symptomatic patients
for transduced cluster of differentiation 34 positive (CD34+) HSC treatment. 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/ABCD1, 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/ALD patients.
Study Phase
Phase 1/Phase 2
Study Type
Interventional
Primary Outcome
The short-term safety and tolerability after hematopoietic stem cell transplanation
Secondary Outcome
immune responses against the transgene(For MLD)
Condition
Metachromatic Leukodystrophy
Intervention
transduced CD34+ hematopoietic stem cell
Study Arms / Comparison Groups
transduced CD34+ hematopoietic stem cell
Description: Transplantation of autologous CD34+ hematopoietic stem cells transduced with ARSA/ABCD1 encoding lentiviral vector. Dosage: 2x10^6/Kg （Minimum）to 20x10^6/Kg （Maximum） transduced CD34+ cells at bedside for infusion
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Genetic
Estimated Enrollment
50
Start Date
January 2015
Completion Date
October 2025
Primary Completion Date
October 2025
Eligibility Criteria
Inclusion Criteria:
Inclusion Criteria For MLD:
1. Confirmed diagnosis as MLD by ARSA genetic diagnosis, MRI（Magnetic Resonance
Imaging）and low ARSA A activity (below 20% of normal level);
2. The patient' symptoms and lesions have not been developed to the end stage of MLD.
Inclusion Criteria For ALD:
1. Confirmed diagnosis as ALD by ABCD1 genetic diagnosis, abnormal MRI imaging, abnormal
high level of very long chain fatty acid (VLCFA) and adrenocorticotropic hormone
(ACTH);
2. The patient' symptoms and lesions have not been developed to the end stage of ALD.
Exclusion Criteria:
Exclusion Criteria For MLD：
1. No clinical symptoms of MLD;
2. ARSA activity >50% compared to healthy individuals;
3. End stage of MLD;
4. Other complications, ie. Cancer;
5. human immunodeficiency virus（HIV） RNA and/or hepatitis C virus RNA and/or hepatitis B
virus DNA positive patients;
6. Patients who underwent allogenic hematopoietic stem cell transplantation with evidence
of residual cells of donor origin.
Exclusion Criteria For ALD:
1. No evidence of brain lesions;
2. Normal level of VLCFAs in blood;
3. End stage of ALD;
4. Other complications, ie. Cancer;
5. human immunodeficiency virus（HIV） RNA and/or hepatitis C virus RNA and/or hepatitis B
virus DNA positive patients;
6. Patients who underwent allogenic hematopoietic stem cell transplantation with evidence
of residual cells of donor origin.
Gender
All
Ages
2 Years - 45 Years
Accepts Healthy Volunteers
No
Contacts
Qizhou Lian, M.D.,Ph.D., +8613923406652, [email protected]
Location Countries
China
Location Countries
China
Administrative Informations
NCT ID
NCT02559830
Organization ID
ChiCTR-OPC-15005802
Responsible Party
Sponsor
Study Sponsor
Shenzhen Second People's Hospital
Collaborators
Shenzhen University
Study Sponsor
Qizhou Lian, M.D.,Ph.D., Principal Investigator, The University of Hong Kong
Verification Date
September 2015