Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

NCT ID: NCT02559830

Last Updated: 2022-05-31

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 50 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-01-31
• Study Completion Date: 2025-10-31

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.

Conditions

Metachromatic Leukodystrophy; Adrenoleukodystrophy

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

transduced CD34+ hematopoietic stem cell

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

Group Type: EXPERIMENTAL

transduced CD34+ hematopoietic stem cell

Intervention Type: GENETIC

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.

Interventions

transduced CD34+ hematopoietic stem cell

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.

Intervention Type: GENETIC

Eligibility Criteria

Inclusion Criteria

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

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

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

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

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 16 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Shenzhen University

OTHER

Sponsor Role: collaborator

Guangzhou Women and Children's Medical Center

OTHER

Sponsor Role: collaborator

Shenzhen Second People's Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Qizhou Lian, M.D.,Ph.D.

Role: PRINCIPAL_INVESTIGATOR

The University of Hong Kong

Jiacai Zhuo

Role: PRINCIPAL_INVESTIGATOR

Shenzhen Second People's Hospital

Xin Du, M.D.,Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Shenzhen Second People's Hospital

Hua Jiang, M.D,Ph.D

Role: PRINCIPAL_INVESTIGATOR

Guangzhou Women and Children's Medical Center

GuangFu Chen, M.D.,Ph.D

Role: PRINCIPAL_INVESTIGATOR

Shenzhen Second People's Hospital

Locations

Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University

Shenzhen, Guangdong, China

Site Status: RECRUITING

Countries

China

Central Contacts

JiaCai zhou, M.D.,Ph.D

Role: CONTACT

jiacai8199@163.com

+8613923406652

Qizhou Lian, M.D.,Ph.D.

Role: CONTACT

dalilian2000@aliyun.com

Facility Contacts

Qizhou Lian

Role: primary

dalilian2000@aliyun.com

+8675583366388

Jiacai Zhuo

Role: backup

jiacai8199@163.com

+8675583366388 ext. 8197

References

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Reference Type: RESULT

PMID: 19892975 (View on PubMed)

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Reference Type: RESULT

PMID: 23845948 (View on PubMed)

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Reference Type: RESULT

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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.

Reference Type: RESULT

PMID: 11399225 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23966770 (View on PubMed)

Other Identifiers

ChiCTR-OPC-15005802

Identifier Type: -

Identifier Source: org_study_id