Gene Therapy for Metachromatic Leukodystrophy (TIGET-MLD)

Study Description

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Brief Summary:

This is a phase I/II protocol aiming at the assessment of the safety and efficacy of ARSA gene transfer into hematopoietic stem/progenitor cells for the treatment of Metachromatic Leukodystrophy.

Condition or disease	Intervention/treatment	Phase
Lysosomal Storage Disease	Genetic: Autologous CD34+ stem cells transduced with ARSA encoding lentiviral vector	Phase 2

Detailed Description:

Metachromatic Leukodystrophy (MLD) is an autosomal recessive Lysosomal Storage Disorder (LSD) characterized by severe and progressive dysmyelination affecting the central and peripheral nervous system.

Hematopoietic cell transplantation (HCT) is ineffective in ameliorating patients' phenotype or delaying disease evolution. No evidences of efficacy of enzyme replacement strategies are available at the moment. Transplantation of genetically corrected autologous hematopoietic stem cells (HSC) could represent a novel and potentially efficacious treatment for MLD patients.

We are conducting a gene therapy clinical trial based on autologous HSC and advanced generation lentiviral vectors (LV) for patients affected by the most severe, early onset forms of the disease, based on our preclinical efficacy and safety data and on the experience we acquired from the treatment of Adenosine deaminase deficiency (ADA-SCID) patients by a similar approach. Our general goal is to demonstrate safety and efficacy of this gene therapy approach in MLD patients. We have developed and tested a clinically applicable LV containing the ARSA cDNA controlled by a constitutive eukaryotic promoter sequence. Preclinical studies aimed at assessing efficacy and safety of ARSA gene transfer using the selected vector have been conducted in the murine model of the disease and in progenitors and mature hematopoietic cells from MLD patients. The following results were obtained:

1. efficient ARSA gene transfer;
2. long term in vitro and in vivo multilineage ARSA expression;
3. ability to prevent and correct neurological disease manifestations;
4. good tolerance and long-term safety of the treatment in the animal model.

We expect to treat 20 patients, selected according to disease severity and clinical features. A myeloablative conditioning regimen based on iv Busulfan will be administered to the patients to enable engraftment of the transduced stem/progenitor cells in the bone marrow and enhance CNS microglia/macrophage repopulation by the transduced cell progeny. An efficient transduction protocol based on LVs has been optimized to guarantee abundant ARSA expression in the transduced patients' HSC and their progeny. In the treated patients, we will study the short-term and long-term safety of the administration of the autologous transduced HSC, their long-term engraftment, the expression of vector-derived ARSA, and the ability of the transduced cells to provide a clinical benefit to the patients. The treated patients will be followed for 3 years and thereafter monitored for the safety of gene therapy for additional 5 years. If successful, this study will provide key results on the safety and efficacy of gene therapy for MLD patients.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	14 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
Study Start Date :	May 2010
Estimated Primary Completion Date :	April 2023
Estimated Study Completion Date :	April 2023

Arms and Interventions

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Intervention Details:

Genetic: Autologous CD34+ stem cells transduced with ARSA encoding lentiviral vector
Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA under the control of the human phosphoglyceratekinase (PGK) promoter. Dose: ≥ 2x10^6 transduced CD34+ cells/Kg (maximum 20x10^6) at bedside for infusion.

Outcome Measures

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Primary Outcome Measures :

1. Conditioning regimen-related safety [ Time Frame: at +60 days after transplantation ]
   The absence of engraftment failure or delayed hematopoietic reconstitution (prolonged
2. Conditioning regimen-related toxicity [ Time Frame: 3 years ]
   The absence of regimen related toxicity, as determined by a surveillance of clinical (NCI >2
3. The short-term safety and tolerability of lentiviral-transduced cell infusion [ Time Frame: 48 hours after transplant ]
   It will be evaluated on the basis of adverse events reporting and monitoring of the systemic
4. 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
5. Increase of residual ARSA activity [ Time Frame: 24 months after treatment ]
   A significant (≥ 2 SD) increase of residual ARSA activity as compared to pretreatment
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, when
3. Transduced cell engraftment [ Time Frame: 12 months after treatment ]
   Transduced cell engraftment above 4% in PBMCs and CD34+ progenitors in BM
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

Eligibility Criteria

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Ages Eligible for Study:	Child, Adult, Senior
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Pre-symptomatic late infantile patients
• Pre- or early-symptomatic early juvenile patients (IQ > 70 and ability to walk independently for >10 steps)
• Parental/guardian/patient signed informed consent.

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

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Locations

Italy
GSK Investigational Site
Milan, Italy, 20132

Sponsors and Collaborators

GlaxoSmithKline

Fondazione Telethon

Investigators

Study Director:	GSK Clinical Trials	GlaxoSmithKline

More Information

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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.

Responsible Party:	GlaxoSmithKline
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:	March 24, 2017
Last Verified:	March 2017

Keywords provided by GlaxoSmithKline:

Lentiviral vector; Metachromatic Leukodystrophy; Gene Therapy

Additional relevant MeSH terms:

Lysosomal Storage Diseases; Leukodystrophy, Metachromatic; 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