Gene Therapy for Metachromatic Leukodystrophy (MLD)

Sponsor

Orchard Therapeutics (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT01560182

Collaborator

Ospedale San Raffaele (Other)

Enrollment

Location

Arm

156

Anticipated Duration (Months)

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Lysosomal Storage Disease Metachromatic Leukodystrophy	Genetic: OTL-200 Gene Therapy	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

N/A

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

Actual Study Start Date :

Apr 9, 2010

Actual Primary Completion Date :

Apr 9, 2018

Anticipated Study Completion Date :

Apr 9, 2023

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: OTL-200 Gene Therapy

CD34+ cells transduced ex vivo with lentiviral vector encoding ARSA cDNA

Genetic: OTL-200 Gene Therapy

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

Other Names:

Previously GSK2696274

Outcome Measures

Primary Outcome Measures

Improvement of GMFM score [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 [24 months after treatment]
A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total PBMC
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
Conditioning regimen-related toxicity [3 years]
The absence of regimen related toxicity, as determined by a surveillance of 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 transplant]
It will be evaluated 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 [baseline and after 1, 3, 6, 12 and 24 months]
Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen

Secondary Outcome Measures

The absence of immune responses against the transgene (immunoblot analyses). [every three months for the first year, then once a year.]
Even if an immune responses against the functional ARSA enzyme is not expected, treated subjects will be monitored for antibodies anti-ARSA on a defined schedule.
Improvement in the NCV Index for ENG and in the total score for MR [24 months after treatment]
An improvement in the NCV Index for ENG and in the total brain MRI score.
Transduced cell engraftment [12 months after treatment]
Transduced cell engraftment above 4% in bone marrow-derived clonogenic progenitor cells. 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 [24, 30 and 36 months after treatment]
The measurement of an IQ above 55 (threshold for severe disability) at neuro-psychological testings

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 7 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
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.