Hematopoietic stem cell gene therapy study

Phase 1/2

Active, not recruiting

• Conditions: Metachromatic Leukodystrophy (MLD)

• Registration Number: 2024-515253-25-00
• Lead Sponsor: Orchard Therapeutics (Europe) Limited

Brief Summary

Evaluation of the safety of gene therapy in MLD subjects, considering both the conditioning regimen safety and the safety of LV-transduced cell infusion, short and long-term after the treatment (for details see safety primary endpoint);"Evaluation of the efficacy of gene therapy, assessed as reduction in the progression of the clinical motor impairment in treated subjects as compared to the progression measured in untreated MLD patients in our disease natural history study, accompanied by a significant increase of residual ARSA activity as compared to pre-treatment subjects’ values. Motor functions will be measured by the clinically relevant GMFM scoring system (for details see efficacy primary endpoint). Indeed, there is a clear causal relationship between the potential beneficial outcome measured with the GMFM and the treatment, being motor impairment consequent to the involvement of both central and peripheral nervous system, and less influenced by other variables. Residual ARSA activity will be measured on hematopoietic cells (PBMC and BM cells)

Detailed Description

Not available

Study Timeline

• Study First Posted: 2024-10-01
• Last Update Posted: 2025-06-04

Recruitment & Eligibility

• Status: Ongoing, recruitment ended
• Sex: Not specified
• Target Recruitment: 20

Inclusion Criteria

Pre-symptomatic late infantile patients;

Pre- or early-symptomatic early juvenile patients;

Parental/guardian/patientsigned informed consent.

Exclusion Criteria

• HIVRNA and/or HCVRNA and/or HBVDNA-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;

• Patients who underwent allogeneic hematopoietic stem cell transplantation in the previous 6 months; • Patients who underwent allogeneic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Safety endpoint- 1. Conditioning regimen-related safety, consisting of the absence of engraftment failure or delayed hematological reconstitution (prolonged aplasia) and surveillance of non-hematological regimen related toxicity (AEs with NCI Common Toxicity Criteria grade ≥ 2; and laboratory parameters with NCI Common Toxicity Criteria grade ≥ 3).		Safety endpoint- 1. Conditioning regimen-related safety, consisting of the absence of engraftment failure or delayed hematological reconstitution (prolonged aplasia) and surveillance of non-hematological regimen related toxicity (AEs with NCI Common Toxicity Criteria grade ≥ 2; and laboratory parameters with NCI Common Toxicity Criteria grade ≥ 3).
2. Safety of LV-transduced cell infusion, defined as: a) short-term safety and tolerability of lentiviraltransduced cell infusion; b) long-term safety of lentiviral-transduced cell infusion (absence of Replication Competent Lentivirus (RCL) and abnormal clonal proliferation).		2. Safety of LV-transduced cell infusion, defined as: a) short-term safety and tolerability of lentiviraltransduced cell infusion; b) long-term safety of lentiviral-transduced cell infusion (absence of Replication Competent Lentivirus (RCL) and abnormal clonal proliferation).
Efficacy endpoints- 1. An improvement of ≥ 10% of the total score at gross motor function measure (GMFM) at comparison with the GMFM scores obtained by aged matched untreated MLD patients, evaluated 24 months after treatment. 2. A significant increase of Arylsulfatase A (ARSA) activity as compared to pre-treatment values, measured in total peripheral blood mononuclear cells 24 months after treatment		Efficacy endpoints- 1. An improvement of ≥ 10% of the total score at gross motor function measure (GMFM) at comparison with the GMFM scores obtained by aged matched untreated MLD patients, evaluated 24 months after treatment. 2. A significant increase of Arylsulfatase A (ARSA) activity as compared to pre-treatment values, measured in total peripheral blood mononuclear cells 24 months after treatment

Secondary Outcome Measures

Name	Time	Method
Safety endpoint- 1. Absence of immune responses against the transgene		Safety endpoint- 1. Absence of immune responses against the transgene
Efficacy Endpoints- o The Nerve Conduction Velocity Index at 24 months after treatment compared to scores observed in the historical control MLD population. Nerve conduction velocity in individual sensory and motor nerves will also be evaluated. o The total brain MRI scores at 24 months after treatment compared to scores observed in the historical control MLD population. o GMFC-MLD levels at different ages in treated subjects compared to the historical control MLD population		Efficacy Endpoints- o The Nerve Conduction Velocity Index at 24 months after treatment compared to scores observed in the historical control MLD population. Nerve conduction velocity in individual sensory and motor nerves will also be evaluated. o The total brain MRI scores at 24 months after treatment compared to scores observed in the historical control MLD population. o GMFC-MLD levels at different ages in treated subjects compared to the historical control MLD population
o The measurement of Intelligence Quotient (IQ) values above 55 at 24, 30 and 36 months after treatment. o An engraftment of the transduced cells above 4% in bone marrowderived clonogenic progenitor cells at 12 months after the transplant. o Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and BM cell subpopulations will also be evaluated. o Evaluation of correlations occurring between transduced cell engraftment levels and busulfan exposure.		o The measurement of Intelligence Quotient (IQ) values above 55 at 24, 30 and 36 months after treatment. o An engraftment of the transduced cells above 4% in bone marrowderived clonogenic progenitor cells at 12 months after the transplant. o Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and BM cell subpopulations will also be evaluated. o Evaluation of correlations occurring between transduced cell engraftment levels and busulfan exposure.

Trial Locations

Locations (1)

Ospedale San Raffaele S.r.l.; 🇮🇹 Milan, Italy

Ospedale San Raffaele S.r.l.

🇮🇹Milan, Italy

Alessandro Aiuti

Site contact

+390226434472

aiuti.alessandro@hsr.it