NCT02559830 - Autologous Hematopoietic Stem Cell Gene Therapy for 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.