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

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.

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