Gene Therapy for Metachromatic Leukodystrophy (MLD)

Orchard Therapeutics20 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Lysosomal Storage Disease Metachromatic Leukodystrophy

Interventions

OTL-200 Gene TherapyGENETIC

Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA

Eligibility

Sex: ALLMax age: 7 Years

Medical Language ↔ Plain English

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.

Locations (1)

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Milan, Italy

Outcomes

Primary Outcomes

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.

Time frame: 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)

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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).

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 12 months after treatment

IQ measurement above 55

The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings

Time frame: 24, 30 and 36 months after treatment