Gene Therapy for Metachromatic Leukodystrophy (MLD)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy

Conditions
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Lysosomal Storage Disease, Metachromatic Leukodystrophy

Intervention / Treatment
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* Genetic: OTL-200 Gene Therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-symptomatic MLD patients with the late infantile variant; Pre- or early-symptomatic MLD patients with the early juvenile variant; Patients for whom parental/guardian signed informed consent has been obtained. Exclusion Criteria: HIV RNA and/or HCV RNA and/or HBV DNA positive patients; Patients affected by neoplastic diseases; Patients with cytogenetic alterations typical of MDS/AML; Patients with end-organ functions or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study; Patients enrolled in other trials/other therapeutic approaches that might become available; Patient who underwent allogeneic hematopoietic stem cell transplantation in the previous six months; Patient who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Ages Eligible for Study
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Maximum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: OTL-200 Gene Therapy<br>CD34+ cells transduced ex vivo with lentiviral vector encoding ARSA cDNA | Genetic: OTL-200 Gene Therapy<br>* Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA<br>* Other names: Previously GSK2696274;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Improvement of Gross Motor Function Measure (GMFM) score | An improvement of 10% of the total GMFM score in treated patients, when compared to the GMFM scores in the historical control MLD population, evaluated 24 months after treatment. | 24 months after treatment | 
| Increase of residual Arylsulfatase A (ARSA) activity | A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total Peripheral Blood Mononuclear Cells (PBMCs) | 24 months after treatment | 
| Conditioning regimen-related safety | 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 (BM) recovery, requiring cellular back-up administration. | at +60 days after transplantation | 
| Conditioning regimen-related toxicity | The absence of regimen related toxicity, as determined by a surveillance of adverse events (AEs) (NCI ≥2) and laboratory parameters (NCI ≥3) 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 | 3 years after treatment | 
| The short-term safety and tolerability of lentiviral-transduced cell infusion | It will be evaluated on the basis of AEs reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash). Evaluation will also consist of the absence of Serious Adverse Reactions (SARs) within 48 hours after infusion. | 48 hours after treatment infusion | 
| The long-term safety of lentiviral-transduced cell infusion | Absence of Replication Competent Lentivirus: Assessed via enzyme-linked immunosorbent assay (ELISA) test for serum human immunodeficiency virus (HIV) p24 antigen. Positive HIV p24 test result is subject to second level testing including: a) DNA PCR for vesicular stomatitis virus G (VSV-G) envelope (PBMC) and b) reverse transcription (RT) PCR for HIV-pol ribonucleic acid (RNA) (plasma). | baseline, 1, 3, 6, and 12 months after treatment, then once a year | 
| The long-term safety of lentiviral-transduced cell infusion | Absence of Abnormal Clonal Proliferation: monitored by clinical and laboratory surveillance, TCR Vβ repertoire analysis, and bone marrow examination. | baseline, 3, 6 and 12 months after treatment, then once a year | 
| The long-term safety of lentiviral-transduced cell infusion | Lentiviral vector integration site analysis will also be performed | 6 and 12 months after treatment, then once a year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The absence of immune responses against the transgene (immunoblot analyses). | Even if immune responses against the functional ARSA enzyme are not expected, treated subjects will be monitored for anti-ARSA antibodies on a defined schedule. | baseline, 3, 6, and 12 months after treatment, then once a year | 
| Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score. | The NCV Index and the total brain MRI score will be compared to scores observed in the historical control MLD population. Gross Motor Function Classification for MLD (GMFC-MLD) levels at different ages compared to the historical control MLD population. | 24 months after treatment | 
| Transduced cell engraftment | Transduced cell engraftment above 4% in bone marrow-derived clonogenic progenitor cells, assessed as the percentage of LV-positive colonies. Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and bone marrow (BM) cell subpopulations will also be evaluated. | 12 months after treatment | 
| IQ measurement above 55 | The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings | 24, 30 and 36 months after treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OTL-200, Metachromatic Leukodystrophy, Gene Therapy, MLD, Previously GSK2696274