Gene Therapy for Metachromatic Leukodystrophy (MLD)

Metachromatic Leukodystrophy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01560182
• Other study ID #: 201222
• Secondary ID: Eudract 2009-017
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: April 9, 2010
• Est. completion date: March 15, 2025

Study information

• Verified date: November 2023
• Source: Orchard Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 20
• Est. completion date: March 15, 2025
• Est. primary completion date: April 9, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 7 Years

Eligibility

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.

Related Conditions & MeSH terms

• Leukodystrophy, Metachromatic
• Lysosomal Storage Disease
• Lysosomal Storage Diseases
• Metachromatic Leukodystrophy

Intervention

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

Locations

Country	Name	City	State
Italy	Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)	Milan

Sponsors (2)

Lead Sponsor	Collaborator
Orchard Therapeutics	Ospedale San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (6)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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
Primary	The long-term safety of lentiviral-transduced cell infusion	Absence of Abnormal Clonal Proliferation: monitored by clinical and laboratory surveillance, TCR Vß repertoire analysis, and bone marrow examination.	baseline, 3, 6 and 12 months after treatment, then once a year
Primary	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	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
Secondary	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
Secondary	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
Secondary	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