Mucopolysaccharidosis type IIIA (Sanfilippo A syndrome) is an inherited lysosomal storage disease caused by a specific lysosomal enzyme deficiency that leads to intracellular accumulation of the GAG heparan sulphate (HS). It is caused by a deficiency of one of the four enzymes involved in the lysosomal degradation of HS. In the case of subtype A is the heparan N-sulfatase (SGSH).
Conditions
Interventions
Product Name: Vector viral adenoasociado de serotipo 9 que contiene el gen de la sulfamidasa humana
Product Code: AAV9-CAG-coh-SGSH
Pharmaceutical Form: Suspension for injection
INN or Proposed INN:
Sponsors
Laboratorios del Dr. Esteve, S.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1.- Male and female patients aged 2 years or older. 2.- Patients with confirmed MPSIIIA (by genotype), with underlying missense mutation at least in one of the alleles for the disease and documented deficiency in sulfamidase enzyme activity of less than or equal to 10%. 3.- Onset of clinical manifestations related to MPSIIIA during the first 6 years of life. 4.- Patients with an adaptive behaviour score between 40 and 90 as evaluated by the Vineland Adaptive Behaviour Scale (Vineland-II). 5.- Patients not dependent on a wheelchair. 6.- Patients without severe sensory deficit (blindness, deafness that requires headset). 7.- Patients with stable symptomatic treatment (depending on weight) within the last 3 months, with no anticipated changes in medication regimen. 8.- Patients with no contraindication for surgical procedure and/or anaesthesia. Patients taking non-steroidal anti-inflammatory drugs (NSAIDs) should discontinue their use. 9.- Patients medically stable to accommodate the protocol requirements, including travelling and assessments. 10.- Signed informed consent. Are the trial subjects under 18? yes Number of subjects for this age range: 6 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1.- Patient deterioration that may compromise the interpretation of the study results. 2.- Patients with neutralising antibodies (NAb) against AAV9 in cerebrospinal fluid. 3.- Epilepsy resistant to treatment. 4.- Patients with significant co-morbid conditions. 5.- Any contraindication for anaesthesia and product administration procedure, including major risk factors for haemorrhage. 6.- Any vaccination 30 days before investigational product administration. 7.- Patients who have received any medication with the objective of modifying the natural course of the disease, i.e. gene transfer agents or enzyme replacement therapy.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The main objective of this study is to determine the safety and tolerability, including the immune response, after Intracerebroventricular administration of a single dose of AAV9-CAG-coh-SGSH in two dosage cohorts of patients with MPSIIIA.;Secondary Objective: To assess the pharmacodynamic profile and the initial efficacy after Intracerebroventricular administration of a single dose of AAV9-CAG-coh-SGSH in two dosage cohorts of patients with MPSIIIA to estimate the dose required to significantly ameliorate the phenotype. To evaluate the correlation between the pharmacodynamic assessments and the clinical evolution, in order to establish the optimal biomarker to assess the evolution / amelioration of the disease. To collect data regarding potential tests that can be evaluation criteria for the subsequent pivotal study. To assess viral shedding.;Timepoint(s) of evaluation of this end point: Neuro/Physical exam: screening (SC), D -1, D1-discharge (DC), week (W) 2 ,4, month (M) 2,2.5, 3, 6, 9, 12, 18, year (Y) 2-5; AEs: SC, D-1, D0, D1- DC, W2,4, M 2, 2.5, 3, 6, 9, 12, 18,Y 2-5; Laboratory tests/ ECG: SC, D-1, DC, W4,M 3, 6, 9, 12, 18, Y2-5; Inflammatory resp: SC, D -1, DC, W4, M 3, 6, 9, 12,18; Humoral Immune resp: SC, D -1, D0, W4, M 3, 6,9, 12, 18, Y 2-5; T-Cell Immune resp: SC, W2 ,4, M 3, 6, 12, Y 3; Vital signs: SC, D -1, D1-DC ,W4, M 3, 6, 9, 12, 18, Y2-5; MRI-S: SC, D2, M12; Hepatic Ultrasonography: SC, W4, M 3, 6, 9, 12, 18, Y 2-5; Sulfamidase activity/ HS levels: SC, W4, M 3, 6, 9 12, 18,Y 2-5; Neuropsychological scales: SC, M 3, 6, 12, 18, Y 2-5; PedsQL: SC, M 6, 12, 18,Y 2-5; Polysomnography, BAEP, elastography: SC, M12,Y2-5; SDSC: SC, W4, M 3, 6, 9, 12, 18,Y 2-5.;Primary end point(s): Safety and Tolerability: All safety and tolerability parameters will be evaluated at regular time points after AAV9-CAG-coh-SGSH product administration and will be assessed by comparison to screening / baseline evaluations. - Physical examination. - Adverse ev | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Not applicable;Timepoint(s) of evaluation of this end point: Not applicable | — |
Countries
Spain
Contacts
Public ContactAdelaida Morte
Laboratorios del Dr. Esteve,S.A.
Outcome results
None listed