Gene Therapy With Modified Autologous Hematopoietic Stem Cells for Patients With Mucopolysaccharidosis Type IIIA
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|ClinicalTrials.gov Identifier: NCT04201405|
Recruitment Status : Active, not recruiting
First Posted : December 17, 2019
Last Update Posted : July 6, 2021
Patients with MPS IIIA have a clinical disorder marked by severe and progressive brain disease and neurological symptoms due to the accumulation of undigested glycosaminoglycans in all cells of the body.
This study will be the first in human clinical trial to explore the safety, tolerability and clinical efficacy of ex vivo gene therapy (autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene) in MPSIIIA patients. Following treatment with the gene therapy patients will be followed up for a minimum of 3 years.
|Condition or disease||Intervention/treatment||Phase|
|Mucopolysaccharidosis Type IIIA||Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene||Phase 1 Phase 2|
MPS IIIA is caused by a deficiency of the heparan-N-sulfatase (SGSH) enzyme, leading to the accumulation of the glycosaminoglycan heparan sulphate in the lysosomes. Untreated patients of MPS IIIA experience rapid and progressive neurologic deterioration. To date, there is no effective disease-modifying treatment for patients suffering from MPS IIIA.
This study aims to recruit 3 to 5 patients with MPS IIIA who satisfy the inclusion and exclusion criteria and provide full consent, between 3 months and 24 months of age. The investigational medicinal product (IMP) will be a cell-based gene therapy that uses genetically modified autologous CD34+ haematopoietic stem cells transduced with a lentiviral vector containing the human SGSH gene. Patients will be followed up for a minimum of 3 years after gene therapy.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||5 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase I-II, Study of Autologous CD34+ Haematopoietic Stem Cells Transduced ex Vivo With CD11b Lentiviral Vector Encoding for Human SGSH in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIa, Sanfilippo Syndrome Type A)|
|Actual Study Start Date :||January 7, 2020|
|Estimated Primary Completion Date :||October 30, 2024|
|Estimated Study Completion Date :||October 30, 2024|
Experimental: Haematopoietic stem cell gene therapy for MPS IIIA
Drug: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene
Autologous CD34+ haematopoietic stem cells from MPS IIIA patients will be genetically modified ex vivo using CD11b.SGSH Lentiviral vector (LV), a self-inactivating LV expressing the SGSH gene codon optimized for human use and regulated by a human CD11b myeloid-specific promoter. Cells will be cryopreserved prior to patient administration.
- To evaluate the tolerability of the IMP in MPS IIIA patients: scale [ Time Frame: up to 3 years ]Adverse events will be recorded and graded according to an adapted Pediatric Clinical Toxicity Scale from the National Institute Allergy and Infectious Diseases (NIAID), Autoimmuno-deficiency Syndrome (AIDS) Division
- To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes [ Time Frame: 12 months post gene therapy ]Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment
- To assess the safety of the IMP in MPS IIIA patients [ Time Frame: up to 3 years ]Presence of replication competent virus and integration events in the leukocytes
- To evaluate overall survival [ Time Frame: up to 3 years ]Overall survival at 36 months post IMP administration compared to natural history data
- To evaluate peripheral engraftment of the IMP [ Time Frame: within 42 days of treatments ]Measured as absence of engraftment failure or delayed hematological reconstitution within the first 6 weeks of IMP delivery. Defined as three independent and consecutive days with absolute Neutrophil Count (ANC) >500/mm3 and/or Platelets >20,000/mm3 without transfusions, and/or Hb >8.0 g/dL without transfusions.
- Change in adaptive behaviour [ Time Frame: up to 3 years (multiple visits) ]Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA
- Change in cognitive function [ Time Frame: up to 3 years (multiple visits) ]Measurement of cognitive score (standard scores, age equivalent scores and development quotient) using the Bayley Scales of Infant Development, 3rd Edition [BSID-III] or Kaufman Assessment Battery for Children, 2nd Edition [KABC-II] against natural history of MPSIIIA
- Change in patient behaviour [ Time Frame: up to 3 years ]Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA
- Change in patient quality of life [ Time Frame: Up to 3 years ]Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA
- Change in patient's daily living [ Time Frame: Up to 3 years ]Measured using the Children sleep Questionnaire against natural history data
- To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine [ Time Frame: 6 months and 12 months post-IMP treatments and multiple other visits over time ]Measure change in ng/ml glycosaminoglycans in CSF from baseline following IMP administration
- To evaluate the effect of the IMP on SGSH activity in CSF, plasma and peripheral blood mononuclear cells. [ Time Frame: 6 months and 12 months post-IMP treatments and multiple other visits over time ]Change in SGSH activity measured from baseline
- To evaluate clinical efficacy of the IMP on brain imaging biomarkers [ Time Frame: up to 3 years ]Measure change in brain volume (total brain, grey and white matter, ventricle volume) by MRI and compare to baseline and natural history data to help assess brain development
- To explore the presence of anti-SGSH antibodies following treatment with the IMP [ Time Frame: up to 3 years ]Measure whether an immune response is generated against the SGSH enzyme
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04201405
|Manchester University NHS Foundation Trust|
|Manchester, United Kingdom, M13 9WL|
|Principal Investigator:||Brian Bigger||The University of Manchester|
|Principal Investigator:||Robert Wynn||MFT|