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Gene Therapy for Metachromatic Leukodystrophy (MLD)

Primary Purpose

Lysosomal Storage Disease, Metachromatic Leukodystrophy

Status
Active
Phase
Phase 1
Locations
Italy
Study Type
Interventional
Intervention
OTL-200 Gene Therapy
Sponsored by
Orchard Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lysosomal Storage Disease focused on measuring OTL-200, Metachromatic Leukodystrophy, Gene Therapy, MLD, Previously GSK2696274

Eligibility Criteria

undefined - 7 Years (Child)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

OTL-200 Gene Therapy

Arm Description

CD34+ cells transduced ex vivo with lentiviral vector encoding ARSA cDNA

Outcomes

Primary Outcome Measures

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.
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)
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.
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
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.
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).
The long-term safety of lentiviral-transduced cell infusion
Absence of Abnormal Clonal Proliferation: monitored by clinical and laboratory surveillance, TCR Vβ repertoire analysis, and bone marrow examination.
The long-term safety of lentiviral-transduced cell infusion
Lentiviral vector integration site analysis will also be performed

Secondary Outcome Measures

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.
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.
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.
IQ measurement above 55
The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings

Full Information

First Posted
March 16, 2012
Last Updated
November 4, 2022
Sponsor
Orchard Therapeutics
Collaborators
Ospedale San Raffaele
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1. Study Identification

Unique Protocol Identification Number
NCT01560182
Brief Title
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

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 9, 2010 (Actual)
Primary Completion Date
April 9, 2018 (Actual)
Study Completion Date
March 15, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Orchard Therapeutics
Collaborators
Ospedale San Raffaele

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lysosomal Storage Disease, Metachromatic Leukodystrophy
Keywords
OTL-200, Metachromatic Leukodystrophy, Gene Therapy, MLD, Previously GSK2696274

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
OTL-200 Gene Therapy
Arm Type
Experimental
Arm Description
CD34+ cells transduced ex vivo with lentiviral vector encoding ARSA cDNA
Intervention Type
Genetic
Intervention Name(s)
OTL-200 Gene Therapy
Other Intervention Name(s)
Previously GSK2696274
Intervention Description
Autologous hematopoietic stem/progenitor cells collected from the bone marrow and transduced ex vivo with a Lentiviral vector encoding the human ARSA cDNA
Primary Outcome Measure Information:
Title
Improvement of Gross Motor Function Measure (GMFM) score
Description
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.
Time Frame
24 months after treatment
Title
Increase of residual Arylsulfatase A (ARSA) activity
Description
A significant increase of residual ARSA activity as compared to pre- treatment values, measured in total Peripheral Blood Mononuclear Cells (PBMCs)
Time Frame
24 months after treatment
Title
Conditioning regimen-related safety
Description
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.
Time Frame
at +60 days after transplantation
Title
Conditioning regimen-related toxicity
Description
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
Time Frame
3 years after treatment
Title
The short-term safety and tolerability of lentiviral-transduced cell infusion
Description
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.
Time Frame
48 hours after treatment infusion
Title
The long-term safety of lentiviral-transduced cell infusion
Description
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).
Time Frame
baseline, 1, 3, 6, and 12 months after treatment, then once a year
Title
The long-term safety of lentiviral-transduced cell infusion
Description
Absence of Abnormal Clonal Proliferation: monitored by clinical and laboratory surveillance, TCR Vβ repertoire analysis, and bone marrow examination.
Time Frame
baseline, 3, 6 and 12 months after treatment, then once a year
Title
The long-term safety of lentiviral-transduced cell infusion
Description
Lentiviral vector integration site analysis will also be performed
Time Frame
6 and 12 months after treatment, then once a year
Secondary Outcome Measure Information:
Title
The absence of immune responses against the transgene (immunoblot analyses).
Description
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.
Time Frame
baseline, 3, 6, and 12 months after treatment, then once a year
Title
Nerve Conduction Velocity (NCV) Index for Electroneurography (ENG) and total brain MRI score.
Description
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.
Time Frame
24 months after treatment
Title
Transduced cell engraftment
Description
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.
Time Frame
12 months after treatment
Title
IQ measurement above 55
Description
The measurement of an IQ above 55 (threshold for severe cognitive impairment) at neuro-psychological testings
Time Frame
24, 30 and 36 months after treatment

10. Eligibility

Sex
All
Maximum Age & Unit of Time
7 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Orchard Clinical Trials
Organizational Affiliation
Orchard Therapeutics
Official's Role
Study Director
Facility Information:
Facility Name
Ospedale San Raffaele - Telethon Institute for Gene Therapy (OSR-TIGET)
City
Milan
ZIP/Postal Code
20132
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
17080200
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.
Results Reference
background
PubMed Identifier
18786133
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.
Results Reference
background
PubMed Identifier
23845948
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.
Results Reference
background
PubMed Identifier
15085191
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.
Results Reference
background
PubMed Identifier
17845130
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.
Results Reference
background
PubMed Identifier
19606494
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.
Results Reference
background
PubMed Identifier
35065785
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.
Results Reference
derived
PubMed Identifier
27289174
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.
Results Reference
derived

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Gene Therapy for Metachromatic Leukodystrophy (MLD)

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