Gene Therapy for Metachromatic Leukodystrophy (MLD)

A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy

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 Overview

• Status: Completed
• Conditions: Lysosomal Storage Disease; Metachromatic Leukodystrophy
• Intervention / Treatment: Genetic: OTL-200 Gene Therapy

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20132
    • Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 3 years (Child)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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)	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.	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	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.	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).	baseline, 1, 3, 6, and 12 months after treatment, then once a year
The long-term safety of lentiviral-transduced cell infusion	Absence of Abnormal Clonal Proliferation: monitored by clinical and laboratory surveillance, TCR Vβ repertoire analysis, and bone marrow examination.	baseline, 3, 6 and 12 months after treatment, then once a year
The long-term safety of lentiviral-transduced cell infusion	Lentiviral vector integration site analysis will also be performed	6 and 12 months after treatment, then once a year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	12 months after treatment
IQ measurement above 55	The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings	24, 30 and 36 months after treatment

Collaborators and Investigators

• Sponsor: Orchard Therapeutics
• Collaborators: Ospedale San Raffaele
• Investigators: Study Director: Orchard Clinical Trials, Orchard Therapeutics

Publications and helpful links

General Publications

• Biffi A, Capotondo A, Fasano S, del Carro U, Marchesini S, Azuma H, Malaguti MC, Amadio S, Brambilla R, Grompe M, Bordignon C, Quattrini A, Naldini L. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Invest. 2006 Nov;116(11):3070-82. doi: 10.1172/JCI28873.
• Biffi A, Cesani M, Fumagalli F, Del Carro U, Baldoli C, Canale S, Gerevini S, Amadio S, Falautano M, Rovelli A, Comi G, Roncarolo MG, Sessa M. Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation. Clin Genet. 2008 Oct;74(4):349-57. doi: 10.1111/j.1399-0004.2008.01058.x. Epub 2008 Sep 11.
• Biffi A, Montini E, Lorioli L, Cesani M, Fumagalli F, Plati T, Baldoli C, Martino S, Calabria A, Canale S, Benedicenti F, Vallanti G, Biasco L, Leo S, Kabbara N, Zanetti G, Rizzo WB, Mehta NA, Cicalese MP, Casiraghi M, Boelens JJ, Del Carro U, Dow DJ, Schmidt M, Assanelli A, Neduva V, Di Serio C, Stupka E, Gardner J, von Kalle C, Bordignon C, Ciceri F, Rovelli A, Roncarolo MG, Aiuti A, Sessa M, Naldini L. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science. 2013 Aug 23;341(6148):1233158. doi: 10.1126/science.1233158. Epub 2013 Jul 11.
• Biffi A, De Palma M, Quattrini A, Del Carro U, Amadio S, Visigalli I, Sessa M, Fasano S, Brambilla R, Marchesini S, Bordignon C, Naldini L. Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J Clin Invest. 2004 Apr;113(8):1118-29. doi: 10.1172/JCI19205.
• Capotondo A, Cesani M, Pepe S, Fasano S, Gregori S, Tononi L, Venneri MA, Brambilla R, Quattrini A, Ballabio A, Cosma MP, Naldini L, Biffi A. Safety of arylsulfatase A overexpression for gene therapy of metachromatic leukodystrophy. Hum Gene Ther. 2007 Sep;18(9):821-36. doi: 10.1089/hum.2007.048.
• Cesani M, Capotondo A, Plati T, Sergi LS, Fumagalli F, Roncarolo MG, Naldini L, Comi G, Sessa M, Biffi A. Characterization of new arylsulfatase A gene mutations reinforces genotype-phenotype correlation in metachromatic leukodystrophy. Hum Mutat. 2009 Oct;30(10):E936-45. doi: 10.1002/humu.21093.
• Fumagalli F, Calbi V, Natali Sora MG, Sessa M, Baldoli C, Rancoita PMV, Ciotti F, Sarzana M, Fraschini M, Zambon AA, Acquati S, Redaelli D, Attanasio V, Miglietta S, De Mattia F, Barzaghi F, Ferrua F, Migliavacca M, Tucci F, Gallo V, Del Carro U, Canale S, Spiga I, Lorioli L, Recupero S, Fratini ES, Morena F, Silvani P, Calvi MR, Facchini M, Locatelli S, Corti A, Zancan S, Antonioli G, Farinelli G, Gabaldo M, Garcia-Segovia J, Schwab LC, Downey GF, Filippi M, Cicalese MP, Martino S, Di Serio C, Ciceri F, Bernardo ME, Naldini L, Biffi A, Aiuti A. Lentiviral haematopoietic stem-cell gene therapy for early-onset metachromatic leukodystrophy: long-term results from a non-randomised, open-label, phase 1/2 trial and expanded access. Lancet. 2022 Jan 22;399(10322):372-383. doi: 10.1016/S0140-6736(21)02017-1.
• Sessa M, Lorioli L, Fumagalli F, Acquati S, Redaelli D, Baldoli C, Canale S, Lopez ID, Morena F, Calabria A, Fiori R, Silvani P, Rancoita PM, Gabaldo M, Benedicenti F, Antonioli G, Assanelli A, Cicalese MP, Del Carro U, Sora MG, Martino S, Quattrini A, Montini E, Di Serio C, Ciceri F, Roncarolo MG, Aiuti A, Naldini L, Biffi A. Lentiviral haemopoietic stem-cell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet. 2016 Jul 30;388(10043):476-87. doi: 10.1016/S0140-6736(16)30374-9. Epub 2016 Jun 8.
• Fumagalli F, Calbi V, Gallo V, Zambon AA, Recupero S, Ciotti F, Sarzana M, Fraschini M, Scarparo S, De Mattia F, Miglietta S, Pierini C, Soncini M, Morena F, Montini E, Barzaghi F, Consiglieri G, Ferrua F, Migliavacca M, Tucci F, Fratini ES, Ippolito A, Silvani P, Calvi MR, Clerici A, Corti A, Facchini M, Locatelli S, Sangalli M, Zancan S, Miotto F, Natali Sora MG, Baldoli C, Martino S, Cordoba-Claros A, Moro SL, Gollop ND, Abate J, Yarzi MN, Nutkins P, Shenker A, Calissano M, Brooks J, Richardson A, Campbell L, Filippi M, Naldini L, Cicalese MP, Ciceri F, Bernardo ME, Aiuti A. Long-Term Effects of Atidarsagene Autotemcel for Metachromatic Leukodystrophy. N Engl J Med. 2025 Apr 24;392(16):1609-1620. doi: 10.1056/NEJMoa2405727.

Study record dates

Study Major Dates

• Study Start (Actual): April 9, 2010
• Primary Completion (Actual): April 9, 2018
• Study Completion (Actual): September 19, 2025

Study Registration Dates

• First Submitted: March 16, 2012
• First Submitted That Met QC Criteria: March 21, 2012
• First Posted (Estimated): March 22, 2012

Study Record Updates

• Last Update Posted (Estimated): December 5, 2025
• Last Update Submitted That Met QC Criteria: December 1, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Keywords: Gene Therapy; OTL-200; MLD; Metachromatic Leukodystrophy; Previously GSK2696274
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Demyelinating Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases, Nervous System; Sphingolipidoses; Lipidoses; Sulfatidosis; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Lysosomal Storage Diseases; Leukodystrophy, Metachromatic
• Other Study ID Numbers: 201222; Eudract 2009-017349-77 (Other Identifier: IRCCS San Raffaele)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No