Gene Therapy for Metachromatic Leukodystrophy (MLD)

• ClinicalTrials.gov Identifier: NCT01560182
• Recruitment Status: Active, not recruiting
• First Posted: March 22, 2012
• Last Update Posted: October 7, 2021
• Sponsor: Orchard Therapeutics
• Collaborator: Ospedale San Raffaele
• Information provided by (Responsible Party): Orchard Therapeutics

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 (Clinical Trial)
• 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: April 9, 2010
• Actual Primary Completion Date: April 9, 2018
• Estimated Study Completion Date: April 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 Name: Previously GSK2696274

Outcome Measures

Primary Outcome Measures :

1. Improvement of GMFM score [ Time Frame: 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.
2. Increase of residual ARSA activity [ Time Frame: 24 months after treatment ]
   A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total PBMC
3. 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
4. Conditioning regimen-related toxicity [ Time Frame: 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
5. The short-term safety and tolerability of lentiviral-transduced cell infusion [ Time Frame: 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
6. The long-term safety of lentiviral-transduced cell infusion [ Time Frame: baseline and after 1, 3, 6, 12 and 24 months ]
   Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen

Secondary Outcome Measures :

1. The absence of immune responses against the transgene (immunoblot analyses). [ Time Frame: 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.
2. Improvement in the NCV Index for ENG and in the total score for MR [ Time Frame: 24 months after treatment ]
   An improvement in the NCV Index for ENG and in the total brain MRI score.
3. Transduced cell engraftment [ Time Frame: 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.
4. IQ measurement above 55 [ Time Frame: 24, 30 and 36 months after treatment ]
   The measurement of an IQ above 55 (threshold for severe disability) at neuro-psychological testings

Eligibility Criteria

• Ages Eligible for Study: up to 7 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.
• 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.

Contacts and Locations

Locations

Italy

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

Milan, Italy, 20132

Sponsors and Collaborators

Orchard Therapeutics

Ospedale San Raffaele

Investigators

• Study Director: Orchard Clinical Trials; Orchard Therapeutics

More Information

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.

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.

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.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Orchard Therapeutics
• ClinicalTrials.gov Identifier: NCT01560182
• Other Study ID Numbers: 201222; Eudract 2009-017349-77 ( Other Identifier: IRCCS San Raffaele )
• First Posted: March 22, 2012
• Last Update Posted: October 7, 2021
• Last Verified: September 2021

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Orchard Therapeutics:

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

Additional relevant MeSH terms:

Leukodystrophy, Metachromatic; Lysosomal Storage Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; 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