Gene Therapy for Metachromatic Leukodystrophy (MLD)

Phase 1

Active, not recruiting

• Conditions: Lysosomal Storage Disease; Metachromatic Leukodystrophy
• Interventions: Genetic: OTL-200 Gene Therapy

• Registration Number: NCT01560182
• Lead Sponsor: Orchard Therapeutics

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2010-04-09
• Study First Submitted: 2012-03-16
• Study First Submitted QC: 2012-03-21
• Study First Posted: 2012-03-22
• Primary Completion: 2018-04-09
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-22
• Last Update Posted: 2023-11-24
• Study Completion: 2025-03-15

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 20

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
OTL-200 Gene Therapy	OTL-200 Gene Therapy	CD34+ cells transduced ex vivo with lentiviral vector encoding ARSA cDNA

Primary Outcome Measures

Name	Time	Method
Conditioning regimen-related safety	at +60 days after transplantation	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.
Increase of residual Arylsulfatase A (ARSA) activity	24 months after treatment	A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total Peripheral Blood Mononuclear Cells (PBMCs)
Improvement of Gross Motor Function Measure (GMFM) score	24 months after treatment	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.
The long-term safety of lentiviral-transduced cell infusion	6 and 12 months after treatment, then once a year	Lentiviral vector integration site analysis will also be performed
Conditioning regimen-related toxicity	3 years after treatment	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
The short-term safety and tolerability of lentiviral-transduced cell infusion	48 hours after treatment 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.

Secondary Outcome Measures

Name	Time	Method
The absence of immune responses against the transgene (immunoblot analyses).	baseline, 3, 6, and 12 months after treatment, then once a year	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.
Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score.	24 months after treatment	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.
Transduced cell engraftment	12 months after treatment	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.
IQ measurement above 55	24, 30 and 36 months after treatment	The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings

Trial Locations

Locations (1)

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET); 🇮🇹 Milan, Italy