Adrenoleukodystrophy Clinical Trial
Official title:
A Phase I/II Clinical Trial of Lentiviral Hematopoietic Stem Cell Gene Therapy for Treatment of Developed Metachromatic Leukodystrophy and Adrenoleukodystrophy
Evaluating the safety and efficacy of Lentiviral Hematopoietic Stem Cell Gene Therapy for advanced stage of Metachromatic Leukodystrophy and adrenoleukodystrophy.
Status | Recruiting |
Enrollment | 50 |
Est. completion date | October 2025 |
Est. primary completion date | October 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 1 Year to 16 Years |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
China | Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University | Shenzhen | Guangdong |
Lead Sponsor | Collaborator |
---|---|
Shenzhen Second People's Hospital | Guangzhou Women and Children's Medical Center, Shenzhen University |
China,
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, Sch — View 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, Lefrère F, Blanche S, Audit M, Payen E, Leboulch P, l'Homme B, Boug — View 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 — View Citation
Matzner U, Schestag F, Hartmann D, Lüllmann-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 c — View 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. Review. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | |
Primary | 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 | |
Primary | 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 | |
Primary | 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 | 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). | up to 8 years | |
Secondary | 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). | up to 8 years | |
Secondary | 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). | up to 8 years | |
Secondary | 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. | up to 8 years | |
Secondary | 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) . | up to 8 years | |
Secondary | 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) . | up to 8 years |
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