Autologous Hematopoietic Stem Cell Gene Therapy for Metachromatic Leukodystrophy and Adrenoleukodystrophy

NCT02559830 | Unknown Phase 1 DMC

• 1 other identifier: ChiCTR-OPC-15005802
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Evaluating the safety and efficacy of Lentiviral Hematopoietic Stem Cell Gene Therapy for advanced stage of Metachromatic Leukodystrophy and adrenoleukodystrophy.

Conditions

Metachromatic Leukodystrophy; Adrenoleukodystrophy

Outcome Measures

Primary Outcomes (4)

• 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.

  2 months

• 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).

  72 hours

• 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).

  72 hours

• 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.

  up to 8 years

Secondary Outcomes (6)

• ARSA activity for MLD

  up to 8 years

• VLCFA level for ALD

  up to 8 years

• Magnetic Resonance imaging (MRI) score

  up to 8 years

• Functional independence measure (FIM) score

  up to 8 years

• Vector copy number (VCN)

  up to 8 years

Study Arms (1)

transduced CD34+ hematopoietic stem cell

EXPERIMENTAL

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

Genetic: transduced CD34+ hematopoietic stem cell

Interventions

transduced CD34+ hematopoietic stem cell 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.

transduced CD34+ hematopoietic stem cell

Eligibility Criteria

• Age: 1 Year - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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;

Sponsors & Collaborators

• Shenzhen Second People's Hospital: lead
• Shenzhen University: collaborator
• Guangzhou Women and Children's Medical Center: collaborator

Study Sites (1)

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

Shenzhen, Guangdong, 518035, China

RECRUITING

Related Publications (5)

• 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.

  PMID: 19892975 RESULT

• 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.

  PMID: 23845948 RESULT

• 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.

  PMID: 11231629 RESULT

• 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.

  PMID: 11399225 RESULT

• 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.

  PMID: 23966770 RESULT

MeSH Terms

Conditions

Leukodystrophy, Metachromatic; Adrenoleukodystrophy

Condition Hierarchy (Ancestors)

Hereditary Central Nervous System Demyelinating Diseases; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sulfatidosis; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Leukoencephalopathies; Demyelinating Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System; Peroxisomal Disorders; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases

Study Officials

• Qizhou Lian, M.D.,Ph.D.

  The University of Hong Kong

  PRINCIPAL INVESTIGATOR

• Jiacai Zhuo

  Shenzhen Second People's Hospital

  PRINCIPAL INVESTIGATOR

• Xin Du, M.D.,Ph.D.

  Shenzhen Second People's Hospital

  PRINCIPAL INVESTIGATOR

• Hua Jiang, M.D,Ph.D

  Guangzhou Women and Children's Medical Center

  PRINCIPAL INVESTIGATOR

• GuangFu Chen, M.D.,Ph.D

  Shenzhen Second People's Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

JiaCai zhou, M.D.,Ph.D

CONTACT

+8613923406652; jiacai8199@163.com

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

CONTACT

dalilian2000@aliyun.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 12, 2015
• First Posted: September 24, 2015
• Study Start: January 1, 2015
• Primary Completion: October 1, 2025
• Study Completion: October 1, 2025
• Last Updated: May 31, 2022

Record last verified: 2016-09

Locations

CN (1)