Open-label, clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein
Name: ABO-102
Description: The incidence, type, and severity of treatment-related adverse events and serious adverse events
Measure: Adverse Events and Serious Adverse Events Time: 24 monthsDescription: Change from baseline in CSF heparan sulfate levels after treatment
Measure: CSF Heparan Sulfate Time: 1, 6, 12, 24 monthsDescription: Change from baseline in liver and/or spleen volumes after treatment, as measured by MRI
Measure: Liver and/or Spleen Volumes Time: 1, 6, 12, 24 monthsDescription: Change from baseline in plasma or urine glycosaminoglycans or heparan sulfate after treatment
Measure: Glycosaminoglycans or Heparan Sulfate Time: 1, 6, 12, 18, 24 monthsDescription: Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels after treatment
Measure: SGSH Enzyme Activity Time: 1, 6, 12, 24 MonthsDescription: Change from baseline in brain volume after treatment, as measured by MRI
Measure: Brain Volume Time: 12, 24 monthsDescription: Change from baseline in the Age Equivalent after treatment compared to Natural History Study data calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, 2nd edition, based on chronological and developmental age
Measure: Age Equivalent Time: 6, 12, 18, 24 monthsDescription: Change from baseline in the Developmental Quotient (DQ) after treatment compared to Natural History Study data calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children, 2nd edition, based on chronological and developmental age
Measure: Mullen Developmental Quotient Time: 6, 12, 18, 24 monthsDescription: Change from baseline in the Cognitive Age Equivalent after treatment compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development - Third edition or the Kaufman Assessment Battery for Children. Second Edition, based on developmental age
Measure: Cognitive Age Equivalent Time: 6, 12, 18, 24 monthsDescription: Change from baseline in the Developmental Quotient after treatment compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development - Third edition or the Kaufman Assessment Battery for Children. Second Edition, based on developmental age
Measure: Bayley Developmental Quotient Time: 6, 12, 18, 24 monthsDescription: Change from baseline in the Adaptive Age Equivalent score after treatment compared to Natural History Study data, as assessed by parent report using the Vineland Adaptive Behavior Scale II Survey form
Measure: Adaptive Age Equivalent Score Time: 6, 12, 18, 24 monthsDescription: Change from baseline in sleep pattern as measured by the modified Children's Sleep Habits Questionnaire (CSHQ)
Measure: Sleep Pattern Time: 6, 12, 18, 24 monthsDescription: Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales total score
Measure: Pediatric Quality of Life Inventory Core Time: 6, 12, 18, 24 monthsDescription: Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4)
Measure: Parent Quality of Life Time: 6, 12, 18, 24 monthsDescription: Change from baseline in gastrointestinal symptoms using the PedsQL™ Gastrointestinal Symptoms Scales
Measure: Pediatric Quality of Life Inventory Gastrointestinal Time: 6, 12, 18, 24 monthsDescription: Parent Global Impression Score at different time points
Measure: Parent Global Impression Score Time: 6, 12, 18, 24 monthsDescription: Clinical Global Impression Improvement Score at different time points.
Measure: Clinical Global Impression Improvement Scale Time: 6, 12, 18, 24 monthsDescription: Change from baseline in Parent Symptoms Score Questionnaire
Measure: Parent Symptoms Score Questionnaire Time: 6, 12, 18, 24 monthsDescription: Change from baseline in Body Mass Index after treatment
Measure: Body Mass Index Time: 6, 12, 18, 24 monthsDescription: Incidence and Change from baseline in abnormalities in standard awake 45-minutes- EEG monitoring
Measure: EEG Monitoring Time: 6, 12, 18, 24 monthsDescription: Detection of the AAV9 viral DNA in plasma, saliva, urine and feces will provide preliminary data for the Environmental Risk Assessment (ERA)
Measure: AAV9 Viral DNA Detection Time: 24 monthsAllocation: N/A
Single Group Assignment
There is one SNP
No detectable or significantly reduced SGSH enzyme activity by leukocyte assay and 2. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene - Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of Infant and Toddler Development - Third Edition) - Must be ambulatory, though may receive assistance with ambulation - Age range of 2 years up to 18 years (excluded) Exclusion Criteria: - Inability to participate in the clinical evaluation as determined by Principal Investigator - Identification of two nonsense or null variants on genetic testing of the SGSH gene - At least one S298P mutation in the SGSH gene - Has evidence of an attenuated phenotype of MPS IIIA - Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics - Active viral infection based on clinical observations - Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer, or precludes the child from participating in the protocol assessments and follow up - Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as determined by ELISA binding immunoassay - Participants with a positive response for the ELISPOT for T-cell responses to AAV9 - Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection - Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy - Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing - Any item (braces, etc.) which would exclude the participant from being able to undergo MRI according to local institutional policy - Any other situation that precludes the participant from undergoing procedures required in this study - Participants with cardiomyopathy or significant congenital heart abnormalities - The presence of significant non-MPS IlIA related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study - Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 for GGT, total bilirubin (except in subjects diagnosed with Gilbert's syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and aPTT - Female participant who is pregnant or demonstrates a positive urine or beta-hCG result at screening assessment (if applicable) - Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone) - Previous treatment by Haematopoietic Stem Cell transplantation - Previous participation in a gene/cell therapy or ERT clinical trial - Participants who are anticipated to undergo a procedure involving anesthesia within 6 months post- drug administration - Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03 Inclusion Criteria: - Diagnosis of MPS IIIA confirmed by the following methods: 1. --- S298P ---
No detectable or significantly reduced SGSH enzyme activity by leukocyte assay and 2. Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene - Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of Infant and Toddler Development - Third Edition) - Must be ambulatory, though may receive assistance with ambulation - Age range of 2 years up to 18 years (excluded) Exclusion Criteria: - Inability to participate in the clinical evaluation as determined by Principal Investigator - Identification of two nonsense or null variants on genetic testing of the SGSH gene - At least one S298P mutation in the SGSH gene - Has evidence of an attenuated phenotype of MPS IIIA - Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics - Active viral infection based on clinical observations - Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer, or precludes the child from participating in the protocol assessments and follow up - Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as determined by ELISA binding immunoassay - Participants with a positive response for the ELISPOT for T-cell responses to AAV9 - Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection - Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy - Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing - Any item (braces, etc.) which would exclude the participant from being able to undergo MRI according to local institutional policy - Any other situation that precludes the participant from undergoing procedures required in this study - Participants with cardiomyopathy or significant congenital heart abnormalities - The presence of significant non-MPS IlIA related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study - Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 for GGT, total bilirubin (except in subjects diagnosed with Gilbert's syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and aPTT - Female participant who is pregnant or demonstrates a positive urine or beta-hCG result at screening assessment (if applicable) - Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone) - Previous treatment by Haematopoietic Stem Cell transplantation - Previous participation in a gene/cell therapy or ERT clinical trial - Participants who are anticipated to undergo a procedure involving anesthesia within 6 months post- drug administration - Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03 MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III Mucopolysaccharidoses Mucopolysaccharidosis III This is an open-label, single dose clinical trial. --- S298P ---