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.
Name: Autologous CD34+ cells transduced with a lentiviral vector containing the human SGSH gene
Description: 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
Measure: To evaluate the tolerability of the IMP in MPS IIIA patients: scale Time: up to 3 yearsDescription: Measured by the expression of SGSH in total leukocytes within or above normal range at 12 months post-IMP treatment
Measure: To evaluate the biological efficacy of IMP post-treatment: expression of SGSH in total leukocytes Time: 12 months post gene therapyDescription: Presence of replication competent virus and integration events in the leukocytes
Measure: To assess the safety of the IMP in MPS IIIA patients Time: up to 3 yearsDescription: Overall survival at 36 months post IMP administration compared to natural history data
Measure: To evaluate overall survival Time: up to 3 yearsDescription: 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.
Measure: To evaluate peripheral engraftment of the IMP Time: within 42 days of treatmentsDescription: Measured using the Vineland Adaptive Behaviour scales against natural history of MPSIIIA
Measure: Change in adaptive behaviour Time: up to 3 years (multiple visits)Description: 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
Measure: Change in cognitive function Time: up to 3 years (multiple visits)Description: Measured using the Sanfilippo Behaviour Rating Scale against natural history of MPSIIIA
Measure: Change in patient behaviour Time: up to 3 yearsDescription: Measured using the Infant Toddler Quality of Life questionnaire against natural history of MPSIIIA
Measure: Change in patient quality of life Time: Up to 3 yearsDescription: Measured using the Children sleep Questionnaire against natural history data
Measure: Change in patient's daily living Time: Up to 3 yearsDescription: Measure change in ng/ml glycosaminoglycans in CSF from baseline following IMP administration
Measure: To evaluate the effect of the IMP on heparan sulphate concentration in cerebrospinal fluid (CSF), plasma and urine Time: 6 months and 12 months post-IMP treatments and multiple other visits over timeDescription: Change in SGSH activity measured from baseline
Measure: To evaluate the effect of the IMP on SGSH activity in CSF, plasma and peripheral blood mononuclear cells. Time: 6 months and 12 months post-IMP treatments and multiple other visits over timeDescription: Measure change in brain volume (total brain, greey and white matter, ventricle volume) by MRI and compare to baseline and natural history data to help assess brain development
Measure: To evaluate clinical efficacy of the IMP on brain imaging biomarkers Time: up to 3 yearsDescription: Measure whether an immune response is generated against the SGSH enzyme
Measure: To explore the presence of anti-SGSH antibodies following treatment with the IMP Time: up to 3 yearsAllocation: N/A
Single Group Assignment
There is one SNP
5. Homozygous or compound heterozygous for the S298P mutation or any other mutation known to be associated to slow-progressing phenotype. --- S298P ---