Gene Therapy for Metachromatic Leukodystrophy (MLD)

• Sponsor: Orchard Therapeutics
• Collaborator: Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
• 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

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	20 participants
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 (≥2 SD) increase of residual ARSA activity as compared to pre- treatment values, measured in PBMC and/or BM progenitors
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 clinical (NCI ≥2) and laboratory (NCI ≥3) parameters 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: 24 months after the treatment ]
   Absence of Replication Competent Lentivirus (RCL): ELISA for HIV p24 antigen

Secondary Outcome Measures :

1. The absence of immune responses against the transgene [ Time Frame: every three months for the first year, then once a year. ]
   Even if we do not expect immune responses against the functional ARSA enzyme,
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 score for MR of ≥ 2 SD
3. Transduced cell engraftment [ Time Frame: 12 months after treatment ]
   Transduced cell engraftment above 4% in PBMCs and CD34+ progenitors in BM. 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

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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

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

Sponsors and Collaborators

Orchard Therapeutics

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

Investigators

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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):

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.

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Responsible Party:	Orchard Therapeutics
ClinicalTrials.gov Identifier:	NCT01560182 History of Changes
Other Study ID Numbers:	201222; Eudract 2009-017349-77 ( Other Identifier: IRCCS San Raffaele )
First Posted:	March 22, 2012
Last Update Posted:	May 20, 2019
Last Verified:	May 2019

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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:

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Leukodystrophy, Metachromatic; Lysosomal Storage 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; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolic Diseases; Lipid Metabolism Disorders