Clinical trial NCT01560182: Gene Therapy for Metachromatic Leukodystrophy (MLD)
Official title: A Phase I/II Clinical Trial of Hematopoietic Stem Cell Gene Therapy for the Treatment of Metachromatic Leukodystrophy
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Lysosomal Storage Disease
Metachromatic Leukodystrophy
Keywords: OTL-200
Metachromatic Leukodystrophy
Gene Therapy
MLD
Previously GSK2696274
Lead sponsor: Orchard Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: Ospedale San Raffaele
First posted: 2012-03-22
Enrollment: 20
Sex: ALL
Maximum age (years): 7
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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/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.

Primary outcomes:
measure: Improvement of Gross Motor Function Measure (GMFM) score
timeFrame: 24 months after treatment
measure: Increase of residual Arylsulfatase A (ARSA) activity
timeFrame: 24 months after treatment
measure: Conditioning regimen-related safety
timeFrame: at +60 days after transplantation
measure: Conditioning regimen-related toxicity
timeFrame: 3 years after treatment
measure: The short-term safety and tolerability of lentiviral-transduced cell infusion
timeFrame: 48 hours after treatment infusion
measure: The long-term safety of lentiviral-transduced cell infusion
timeFrame: baseline, 1, 3, 6, and 12 months after treatment, then once a year
measure: The long-term safety of lentiviral-transduced cell infusion
timeFrame: baseline, 3, 6 and 12 months after treatment, then once a year
measure: The long-term safety of lentiviral-transduced cell infusion
timeFrame: 6 and 12 months after treatment, then once a year
Secondary outcomes:
measure: The absence of immune responses against the transgene (immunoblot analyses).
timeFrame: baseline, 3, 6, and 12 months after treatment, then once a year
measure: Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score.
timeFrame: 24 months after treatment
measure: Transduced cell engraftment
timeFrame: 12 months after treatment
measure: IQ measurement above 55
timeFrame: 24, 30 and 36 months after treatment
Other outcomes:
Locations:
city: Milan
country: Italy
facility: Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
Study officials:
affiliation: Orchard Therapeutics
name: Orchard Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
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.
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.
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.
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.
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.
citation: 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.
citation: 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.