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Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02559830
Recruitment Status : Recruiting
First Posted : September 24, 2015
Last Update Posted : May 31, 2022
Sponsor:
Collaborators:
Shenzhen University
Guangzhou Women and Children's Medical Center
Information provided by (Responsible Party):
Shenzhen Second People's Hospital

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

Condition or disease Intervention/treatment Phase
Metachromatic Leukodystrophy Adrenoleukodystrophy Genetic: transduced CD34+ hematopoietic stem cell Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 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 Lentiviral Hematopoietic Stem Cell Gene Therapy for Treatment of Developed Metachromatic Leukodystrophy and Adrenoleukodystrophy
Study Start Date : January 2015
Estimated Primary Completion Date : October 2025
Estimated Study Completion Date : October 2025


Arm Intervention/treatment
Experimental: transduced CD34+ hematopoietic stem cell
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
Genetic: transduced CD34+ hematopoietic stem cell
Autologous hematopoietic stem cells (HSCs) collected from the mobilized peripheral blood and transduced ex vivo with a Lentiviral vector encoding the human ARSA(for MLD)/ABCD1(for ALD) cDNA(complementary DNA). Dose: ≥ 2x10^6 transduced CD34+ cells/Kg (maximum 20x10^6) at bedside for infusion.




Primary Outcome Measures :
  1. 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.

  2. 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).

  3. 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).

  4. The long-term safety safety after hematopoietic stem cell transplanation [ Time Frame: up to 8 years ]
    The absence of adverse affects in the long-term follow-up of HSCGT-treated patients, like hematopoietic system disease.


Secondary Outcome Measures :
  1. ARSA activity for MLD [ Time Frame: up to 8 years ]
    Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), residual ARSA activity (nmol/mg Prot/hr) measured in peripheral blood mononuclear cell (PBMC) and/or bone marrow progenitors will be tested (For MLD).

  2. VLCFA level for ALD [ Time Frame: up to 8 years ]
    Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), very long chain fatty acid(VLCFA) level ( C22,C24,C26 ,nmol/ml; C24/C22; C26/C22) in plasma will be measured (For ALD).

  3. Magnetic Resonance imaging (MRI) score [ Time Frame: up to 8 years ]
    Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), a detailed demerit scoring (0-34 points) developed by Dr. Loes will be performed in determining the extent of myelin injury in brain (eg, very early stage = MRI score 1-3; early stage = MRI score 4-8; late stage = MRI score 9-13; very late stage = MRI score greater than 13).

  4. Functional independence measure (FIM) score [ Time Frame: up to 8 years ]
    Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), a detailed FIM scores will be performed in determining the affect that neurodegeneration impair patients' independence for self-care.

  5. Vector copy number (VCN) [ Time Frame: up to 8 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), PBMCs from periheral blood will be seperated and DNA will be extracted, the VCN per cells will be investigated according to previosu publications by Biffi et al (Science,2013) .

  6. Genomic lentiviral integration sites (Optional) [ Time Frame: up to 8 years ]
    Before and after transplantation 1/2 year , 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), peripheral blood mononuclear cell (PBMCs) from periheral blood will be seperated and DNA will be extracted, genomic lentiviral integration sites will be investigated according to previosu publications by Biffi etal (Science,2013) .



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Ages Eligible for Study:   1 Year to 16 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  3. age < 16.0 years at symptom onset

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.
  3. age < 16.0 years at symptom onset

Exclusion Criteria:

Exclusion Criteria For MLD:

  1. At a pre-symptomatic stage of 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.
  7. Serious organ dysfunction;
  8. were enrolled in other clinical trials in the 6 months prior to screening;
  9. had any other concern that hampered the compliance or safety as judged by the investigator;
  10. Adult

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.
  7. Serious organ dysfunction;
  8. were enrolled in other clinical trials in the 6 months prior to screening;
  9. had any other concern that hampered the compliance or safety as judged by the investigator;
  10. Adult

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): NCT02559830


Contacts
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Contact: JiaCai zhou, M.D.,Ph.D +8613923406652 jiacai8199@163.com
Contact: Qizhou Lian, M.D.,Ph.D. dalilian2000@aliyun.com

Locations
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China, Guangdong
Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University Recruiting
Shenzhen, Guangdong, China, 518035
Contact: Qizhou Lian    +8675583366388    dalilian2000@aliyun.com   
Contact: Jiacai Zhuo    +8675583366388 ext 8197    jiacai8199@163.com   
Sponsors and Collaborators
Shenzhen Second People's Hospital
Shenzhen University
Guangzhou Women and Children's Medical Center
Investigators
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Principal Investigator: Qizhou Lian, M.D.,Ph.D. The University of Hong Kong
Principal Investigator: Jiacai Zhuo Shenzhen Second People's Hospital
Principal Investigator: Xin Du, M.D.,Ph.D. Shenzhen Second People's Hospital
Principal Investigator: Hua Jiang, M.D,Ph.D Guangzhou Women and Children's Medical Center
Principal Investigator: GuangFu Chen, M.D.,Ph.D Shenzhen Second People's Hospital
Publications of Results:

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Responsible Party: Shenzhen Second People's Hospital
ClinicalTrials.gov Identifier: NCT02559830    
Other Study ID Numbers: ChiCTR-OPC-15005802
First Posted: September 24, 2015    Key Record Dates
Last Update Posted: May 31, 2022
Last Verified: September 2016
Additional relevant MeSH terms:
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Adrenoleukodystrophy
Leukodystrophy, Metachromatic
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Hereditary Central Nervous System Demyelinating Diseases
Leukoencephalopathies
Demyelinating Diseases
Mental Retardation, X-Linked
Intellectual Disability
Neurobehavioral Manifestations
Neurologic Manifestations
Genetic Diseases, X-Linked
Genetic Diseases, Inborn
Heredodegenerative Disorders, Nervous System
Metabolism, Inborn Errors
Peroxisomal Disorders
Metabolic Diseases
Adrenal Insufficiency
Adrenal Gland Diseases
Endocrine System Diseases
Sulfatidosis
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Lipid Metabolism Disorders