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Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

Primary Purpose

Metachromatic Leukodystrophy, Adrenoleukodystrophy

Status
Recruiting
Phase
Phase 1
Locations
China
Study Type
Interventional
Intervention
transduced CD34+ hematopoietic stem cell
Sponsored by
Shenzhen Second People's Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Metachromatic Leukodystrophy

Eligibility Criteria

1 Year - 16 Years (Child)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Inclusion Criteria For MLD:

  1. Confirmed diagnosis as MLD by ARSA genetic diagnosis, MRI(Magnetic Resonance Imaging)and low ARSA A activity (below 20% of normal level);
  2. The patient' symptoms and lesions have not been developed to the end stage of MLD.
  3. age < 16.0 years at symptom onset

Inclusion Criteria For ALD:

  1. Confirmed diagnosis as ALD by ABCD1 genetic diagnosis, abnormal MRI imaging, abnormal high level of very long chain fatty acid (VLCFA) and adrenocorticotropic hormone (ACTH);
  2. The patient' symptoms and lesions have not been developed to the end stage of ALD.
  3. age < 16.0 years at symptom onset

Exclusion Criteria:

Exclusion Criteria For MLD:

  1. At a pre-symptomatic stage of of MLD;
  2. ARSA activity >50% compared to healthy individuals;
  3. End stage of MLD;
  4. Other complications, ie. Cancer;
  5. human immunodeficiency virus(HIV) RNA and/or hepatitis C virus RNA and/or hepatitis B virus DNA positive patients;
  6. Patients who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.
  7. Serious organ dysfunction;
  8. were enrolled in other clinical trials in the 6 months prior to screening;
  9. had any other concern that hampered the compliance or safety as judged by the investigator;
  10. Adult

Exclusion Criteria For ALD:

  1. No evidence of brain lesions;
  2. Normal level of VLCFAs in blood;
  3. End stage of ALD;
  4. Other complications, ie. Cancer;
  5. human immunodeficiency virus(HIV) RNA and/or hepatitis C virus RNA and/or hepatitis B virus DNA positive patients;
  6. Patients who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.
  7. Serious organ dysfunction;
  8. were enrolled in other clinical trials in the 6 months prior to screening;
  9. had any other concern that hampered the compliance or safety as judged by the investigator;
  10. Adult

Sites / Locations

  • Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

transduced CD34+ hematopoietic stem cell

Arm Description

Transplantation of autologous CD34+ hematopoietic stem cells transduced with ARSA/ABCD1 encoding lentiviral vector. Dosage: 2x10^6/Kg (Minimum)to 20x10^6/Kg (Maximum) transduced CD34+ cells at bedside for infusion

Outcomes

Primary Outcome Measures

The short-term safety and tolerability after hematopoietic stem cell transplanation
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 recovery, requiring cellular back-up administration.
Incidence of Treatment-Emergent Adverse Events(For MLD)
It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
Incidence of Treatment-Emergent Adverse Events(For ALD)
It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
The long-term safety safety after hematopoietic stem cell transplanation
The absence of adverse affects in the long-term follow-up of HSCGT-treated patients, like hematopoietic system disease.

Secondary Outcome Measures

ARSA activity for MLD
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), residual ARSA activity (nmol/mg Prot/hr) measured in peripheral blood mononuclear cell (PBMC) and/or bone marrow progenitors will be tested (For MLD).
VLCFA level for ALD
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), very long chain fatty acid(VLCFA) level ( C22,C24,C26 ,nmol/ml; C24/C22; C26/C22) in plasma will be measured (For ALD).
Magnetic Resonance imaging (MRI) score
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), a detailed demerit scoring (0-34 points) developed by Dr. Loes will be performed in determining the extent of myelin injury in brain (eg, very early stage = MRI score 1-3; early stage = MRI score 4-8; late stage = MRI score 9-13; very late stage = MRI score greater than 13).
Functional independence measure (FIM) score
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), a detailed FIM scores will be performed in determining the affect that neurodegeneration impair patients' independence for self-care.
Vector copy number (VCN)
Before and after transplantation 1/2 year , 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), PBMCs from periheral blood will be seperated and DNA will be extracted, the VCN per cells will be investigated according to previosu publications by Biffi et al (Science,2013) .
Genomic lentiviral integration sites (Optional)
Before and after transplantation 1/2 year , 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), peripheral blood mononuclear cell (PBMCs) from periheral blood will be seperated and DNA will be extracted, genomic lentiviral integration sites will be investigated according to previosu publications by Biffi etal (Science,2013) .

Full Information

First Posted
August 12, 2015
Last Updated
May 25, 2022
Sponsor
Shenzhen Second People's Hospital
Collaborators
Shenzhen University, Guangzhou Women and Children's Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT02559830
Brief Title
Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy
Official Title
A Phase I/II Clinical Trial of Lentiviral Hematopoietic Stem Cell Gene Therapy for Treatment of Developed Metachromatic Leukodystrophy and Adrenoleukodystrophy
Study Type
Interventional

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Recruiting
Study Start Date
January 2015 (undefined)
Primary Completion Date
October 2025 (Anticipated)
Study Completion Date
October 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shenzhen Second People's Hospital
Collaborators
Shenzhen University, Guangzhou Women and Children's Medical Center

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Evaluating the safety and efficacy of Lentiviral Hematopoietic Stem Cell Gene Therapy for advanced stage of Metachromatic Leukodystrophy and adrenoleukodystrophy.
Detailed Description
This is a phase I/II protocol aiming at the assessment of the safety and efficacy of arylsulfatase A(ARSA) / adenosine-triphosphate-binding cassette, sub-family D (ABCD1) gene transfer into hematopoietic stem/progenitor cells for the treatment of metachromatic leukodystrophy/adrenoleukodystrophy. Metachromatic Leukodystrophy (MLD) is an autosomal recessive Lysosomal Storage Disorder (LSD) characterized by severe and progressive dysmyelination affecting the central and peripheral nervous system. Adrenoleukodystrophy (also known as X-linked adrenoleukodystrophy, ALD, X-ALD), a disorder of peroxisomal fatty acid beta oxidation which results in the accumulation of very-long chain fatty acids (VLCFA) in tissues throughout the body, is caused by mutations in ABCD1.Both diseases are characterized by progressive neurodegenerative decline, leading to a devastating state without treatment. Hematopoietic cell transplantation (HCT) is ineffective in ameliorating patients' phenotype or delaying disease evolution in many patients. 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/ALD patients. Recently, an Italian group conducted 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 (ClinicalTrials.gov Identifier: NCT01560182).The safety and efficacy of this gene therapy approach in MLD patients was evaluated.During 3 years of follow-up, they reported multilineage ARSA expression and ability to prevent and correct neurological disease manifestations.However, only pre-symptomatic late infantile/Pre- or early-symptomatic early juvenile patients were recruited into the trial. In most cases, MLD/ALD patients tend to be diagnosed at an advanced stage, missing the best timing of curable HSC intervention. In our study, we intend to recruit symptomatic patients for transduced cluster of differentiation 34 positive (CD34+) HSC treatment. 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/ABCD1, 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/ALD patients.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metachromatic Leukodystrophy, Adrenoleukodystrophy

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
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
transduced CD34+ hematopoietic stem cell
Arm Type
Experimental
Arm Description
Transplantation of autologous CD34+ hematopoietic stem cells transduced with ARSA/ABCD1 encoding lentiviral vector. Dosage: 2x10^6/Kg (Minimum)to 20x10^6/Kg (Maximum) transduced CD34+ cells at bedside for infusion
Intervention Type
Genetic
Intervention Name(s)
transduced CD34+ hematopoietic stem cell
Intervention Description
Autologous hematopoietic stem cells (HSCs) collected from the mobilized peripheral blood and transduced ex vivo with a Lentiviral vector encoding the human ARSA(for MLD)/ABCD1(for ALD) cDNA(complementary DNA). Dose: ≥ 2x10^6 transduced CD34+ cells/Kg (maximum 20x10^6) at bedside for infusion.
Primary Outcome Measure Information:
Title
The short-term safety and tolerability after hematopoietic stem cell transplanation
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 recovery, requiring cellular back-up administration.
Time Frame
2 months
Title
Incidence of Treatment-Emergent Adverse Events(For MLD)
Description
It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
Time Frame
72 hours
Title
Incidence of Treatment-Emergent Adverse Events(For ALD)
Description
It will be evaluated on the basis of adverse events reporting and monitoring of the systemic reactions to cell infusion (fever, tachycardia, nausea and vomiting, joint pain, skin rash).
Time Frame
72 hours
Title
The long-term safety safety after hematopoietic stem cell transplanation
Description
The absence of adverse affects in the long-term follow-up of HSCGT-treated patients, like hematopoietic system disease.
Time Frame
up to 8 years
Secondary Outcome Measure Information:
Title
ARSA activity for MLD
Description
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), residual ARSA activity (nmol/mg Prot/hr) measured in peripheral blood mononuclear cell (PBMC) and/or bone marrow progenitors will be tested (For MLD).
Time Frame
up to 8 years
Title
VLCFA level for ALD
Description
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), very long chain fatty acid(VLCFA) level ( C22,C24,C26 ,nmol/ml; C24/C22; C26/C22) in plasma will be measured (For ALD).
Time Frame
up to 8 years
Title
Magnetic Resonance imaging (MRI) score
Description
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), a detailed demerit scoring (0-34 points) developed by Dr. Loes will be performed in determining the extent of myelin injury in brain (eg, very early stage = MRI score 1-3; early stage = MRI score 4-8; late stage = MRI score 9-13; very late stage = MRI score greater than 13).
Time Frame
up to 8 years
Title
Functional independence measure (FIM) score
Description
Before and after transplantation 1/2 year, 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), a detailed FIM scores will be performed in determining the affect that neurodegeneration impair patients' independence for self-care.
Time Frame
up to 8 years
Title
Vector copy number (VCN)
Description
Before and after transplantation 1/2 year , 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), PBMCs from periheral blood will be seperated and DNA will be extracted, the VCN per cells will be investigated according to previosu publications by Biffi et al (Science,2013) .
Time Frame
up to 8 years
Title
Genomic lentiviral integration sites (Optional)
Description
Before and after transplantation 1/2 year , 1 year, 3 years, 5 years, and 8 years (all time points are between plus or minus 0.5 years), peripheral blood mononuclear cell (PBMCs) from periheral blood will be seperated and DNA will be extracted, genomic lentiviral integration sites will be investigated according to previosu publications by Biffi etal (Science,2013) .
Time Frame
up to 8 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Maximum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Inclusion Criteria For MLD: Confirmed diagnosis as MLD by ARSA genetic diagnosis, MRI(Magnetic Resonance Imaging)and low ARSA A activity (below 20% of normal level); The patient' symptoms and lesions have not been developed to the end stage of MLD. age < 16.0 years at symptom onset Inclusion Criteria For ALD: Confirmed diagnosis as ALD by ABCD1 genetic diagnosis, abnormal MRI imaging, abnormal high level of very long chain fatty acid (VLCFA) and adrenocorticotropic hormone (ACTH); The patient' symptoms and lesions have not been developed to the end stage of ALD. age < 16.0 years at symptom onset Exclusion Criteria: Exclusion Criteria For MLD: At a pre-symptomatic stage of of MLD; ARSA activity >50% compared to healthy individuals; End stage of MLD; Other complications, ie. Cancer; human immunodeficiency virus(HIV) RNA and/or hepatitis C virus RNA and/or hepatitis B virus DNA positive patients; Patients who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin. Serious organ dysfunction; were enrolled in other clinical trials in the 6 months prior to screening; had any other concern that hampered the compliance or safety as judged by the investigator; Adult Exclusion Criteria For ALD: No evidence of brain lesions; Normal level of VLCFAs in blood; End stage of ALD; Other complications, ie. Cancer; human immunodeficiency virus(HIV) RNA and/or hepatitis C virus RNA and/or hepatitis B virus DNA positive patients; Patients who underwent allogenic hematopoietic stem cell transplantation with evidence of residual cells of donor origin. Serious organ dysfunction; were enrolled in other clinical trials in the 6 months prior to screening; had any other concern that hampered the compliance or safety as judged by the investigator; Adult
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
JiaCai zhou, M.D.,Ph.D
Phone
+8613923406652
Email
jiacai8199@163.com
First Name & Middle Initial & Last Name or Official Title & Degree
Qizhou Lian, M.D.,Ph.D.
Email
dalilian2000@aliyun.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Qizhou Lian, M.D.,Ph.D.
Organizational Affiliation
The University of Hong Kong
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jiacai Zhuo
Organizational Affiliation
Shenzhen Second People's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Xin Du, M.D.,Ph.D.
Organizational Affiliation
Shenzhen Second People's Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Hua Jiang, M.D,Ph.D
Organizational Affiliation
Guangzhou Women and Children's Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
GuangFu Chen, M.D.,Ph.D
Organizational Affiliation
Shenzhen Second People's Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University
City
Shenzhen
State/Province
Guangdong
ZIP/Postal Code
518035
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Qizhou Lian
Phone
+8675583366388
Email
dalilian2000@aliyun.com
First Name & Middle Initial & Last Name & Degree
Jiacai Zhuo
Phone
+8675583366388
Ext
8197
Email
jiacai8199@163.com

12. IPD Sharing Statement

Citations:
PubMed Identifier
19892975
Citation
Cartier N, Hacein-Bey-Abina S, Bartholomae CC, Veres G, Schmidt M, Kutschera I, Vidaud M, Abel U, Dal-Cortivo L, Caccavelli L, Mahlaoui N, Kiermer V, Mittelstaedt D, Bellesme C, Lahlou N, Lefrere F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Bougneres P, Von Kalle C, Fischer A, Cavazzana-Calvo M, Aubourg P. Hematopoietic stem cell gene therapy with a lentiviral vector in X-linked adrenoleukodystrophy. Science. 2009 Nov 6;326(5954):818-23. doi: 10.1126/science.1171242.
Results Reference
result
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
result
PubMed Identifier
11231629
Citation
Consiglio A, Quattrini A, Martino S, Bensadoun JC, Dolcetta D, Trojani A, Benaglia G, Marchesini S, Cestari V, Oliverio A, Bordignon C, Naldini L. In vivo gene therapy of metachromatic leukodystrophy by lentiviral vectors: correction of neuropathology and protection against learning impairments in affected mice. Nat Med. 2001 Mar;7(3):310-6. doi: 10.1038/85454.
Results Reference
result
PubMed Identifier
11399225
Citation
Matzner U, Schestag F, Hartmann D, Lullmann-Rauch R, D'Hooge R, De Deyn PP, Gieselmann V. Bone marrow stem cell gene therapy of arylsulfatase A-deficient mice, using an arylsulfatase A mutant that is hypersecreted from retrovirally transduced donor-type cells. Hum Gene Ther. 2001 Jun 10;12(9):1021-33. doi: 10.1089/104303401750214258.
Results Reference
result
PubMed Identifier
23966770
Citation
Patil SA, Maegawa GH. Developing therapeutic approaches for metachromatic leukodystrophy. Drug Des Devel Ther. 2013 Aug 8;7:729-45. doi: 10.2147/DDDT.S15467. eCollection 2013.
Results Reference
result

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Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

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