Gene Therapy for Metachromatic Leukodystrophy (MLD)

NCT01560182 | Completed Phase 1

• 2 other identifiers: 201222Eudract 2009-017349-77
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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.

Conditions

Lysosomal Storage Disease; Metachromatic Leukodystrophy

Keywords

OTL-200; Metachromatic Leukodystrophy; Gene Therapy; MLD; Previously GSK2696274

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (4)

• 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

Study Arms (1)

OTL-200 Gene Therapy

EXPERIMENTAL

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

Genetic: OTL-200 Gene Therapy

Interventions

OTL-200 Gene Therapy GENETIC

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

Also known as: Previously GSK2696274

OTL-200 Gene Therapy

Eligibility Criteria

• Age: Up to 7 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Orchard Therapeutics: lead
• Ospedale San Raffaele: collaborator

Study Sites (1)

Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)

Milan, 20132, Italy

Location

Related Publications (9)

• 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.

  PMID: 17080200 BACKGROUND

• 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.

  PMID: 18786133 BACKGROUND

• 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.

  PMID: 23845948 BACKGROUND

• 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.

  PMID: 15085191 BACKGROUND

• 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.

  PMID: 17845130 BACKGROUND

• 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.

  PMID: 19606494 BACKGROUND

• 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.

  PMID: 40267426 DERIVED

• 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.

  PMID: 35065785 DERIVED

• 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.

  PMID: 27289174 DERIVED

MeSH Terms

Conditions

Lysosomal Storage Diseases; Leukodystrophy, Metachromatic

Condition Hierarchy (Ancestors)

Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Lipidoses; Lipid Metabolism, Inborn Errors; Lipid Metabolism Disorders

Study Officials

• Orchard Clinical Trials

  Orchard Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 16, 2012
• First Posted: March 22, 2012
• Study Start: April 9, 2010
• Primary Completion: April 9, 2018
• Study Completion: September 19, 2025
• Last Updated: December 5, 2025

Record last verified: 2025-12

Locations

IT (1)