Metachromatic leukodystrophy (MLD) is a rare and life-threatening inherited disease of the body’s metabolic system occurring in approximately one in every 100,000 live births in the U.S. MLD is caused by a mutation in the arylsulfatase-A (ARSA) gene that results in the accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. Currently, there are no approved treatments for MLD. In its late infantile form, mortality at 5 years from onset is estimated at 50% and 44% at 10 years for juvenile patients.
OTL-200 (autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells (HSPC) transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A (ARSA) gene) is an investigational therapy being studied for the treatment of MLD in certain patients. OTL-200 was acquired from GSK in April 2018 and originated from a pioneering collaboration between GSK and the Hospital San Raffaele and Fondazione Telethon, acting through their joint San Raffaele-Telethon Institute for Gene Therapy in Milan, initiated in 2010.
Regulatory Status: U.S. Food and Drug Administration (FDA) has cleared the company’s Investigational New Drug (IND) application for OTL-200, an autologous, hematopoietic stem cell, lentiviral vector-based gene therapy in development for the treatment of metachromatic leukodystrophy (MLD).
This Phase I/II clinical trial consists of the application of lentiviral vector-based gene therapy to patients affected by Metachromatic Leukodystrophy (MLD), a rare inherited Lysosomal Storage Disorder (LSD) resulting from mutations in the gene encoding the Arylsulfatase A (ARSA) enzyme. The medicinal product consists of autologous CD34+ hematopoietic stem/progenitor cells in which a functional ARSA cDNA is introduced by means of 3rd generation VSV-G pseudotyped lentiviral vectors.
Collaborator: Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA
Study Type: Interventional (Clinical Trial)
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy
Primary Outcome Measures:
- Improvement of GMFM score [ Time Frame: 24 months after treatment ]. An improvement of 10% of the total GMFM score in treated patients, when compared to the the GMFM scores in the historical control MLD population, evaluated 24 months after treatment.
- Increase of residual ARSA activity [ Time Frame: 24 months after treatment ], A significant (≥2 SD) increase of residual ARSA activity as compared to pre- treatment values, measured in PBMC and/or BM progenitors
- Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]. The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged aplasia), defined as Absolute Neutrophil Count (ANC)<500/µl
- Conditioning regimen-related toxicity [ Time Frame: 3 years ]. The absence of regimen related toxicity, as determined by a surveillance of clinical (NCI ≥2) and laboratory (NCI ≥3) parameters that will be applied in the short- and long-term follow-up of the treated patients in order to assess the degree of morbidity associated to the conditioning regimen
- The short-term safety and tolerability of lentiviral-transduced cell infusion [ Time Frame: 48 hours after transplant ]. It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion
- The long-term safety of lentiviral-transduced cell infusion [ Time Frame: 24 months after the treatment ]. Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen
Secondary Outcome Measures :
- The absence of immune responses against the transgene [ Time Frame: every three months for the first year, then once a year. ]. Even if we do not expect immune responses against the functional ARSA enzyme
- Improvement in the NCV Index for ENG and in the total score for MR [ Time Frame: 24 months after treatment ]. An improvement in the NCV Index for ENG and in the total score for MR of ≥ 2 SD
- Transduced cell engraftment [ Time Frame: 12 months after treatment ]. Transduced cell engraftment above 4% in PBMCs and CD34+ progenitors in BM. Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and BM cell subpopulations will also be evaluated.
- IQ measurement above 55 [ Time Frame: 24, 30 and 36 months after treatment ]. The measurement of an IQ above 55 (threshold for severe disability) at neuro-psychological testings
Key Finding: Ongoing