Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

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

 ARSA activity 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

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.

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

Gender

All

Ages

1 Year - 16 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 2016