A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy
Overview
- Phase
- Phase 1
- Intervention
- Not specified
- Conditions
- Lysosomal Storage Disease
- Sponsor
- Orchard Therapeutics
- Enrollment
- 20
- Locations
- 1
- Primary Endpoint
- Conditioning regimen-related safety
- Status
- Completed
- Last Updated
- 4 months ago
Overview
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.
Investigators
Eligibility Criteria
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.
Outcomes
Primary Outcomes
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, with no evidence of Bone Marrow (BM) recovery, requiring cellular back-up administration.
Increase of residual Arylsulfatase A (ARSA) activity
Time Frame: 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
Time Frame: 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
Time Frame: 6 and 12 months after treatment, then once a year
Lentiviral vector integration site analysis will also be performed
Conditioning regimen-related toxicity
Time Frame: 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
Time Frame: 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 Outcomes
- The absence of immune responses against the transgene (immunoblot analyses).(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.(24 months after treatment)
- Transduced cell engraftment(12 months after treatment)
- IQ measurement above 55(24, 30 and 36 months after treatment)