Gene Transfer Clinical Trial for Mucopolysaccharidosis (MPS) IIIB

Adeno-associated virus serotype 9 carrying the human NAGLU gene under the control of a CMV enhancer/promoter (rAAV9.CMV.hNAGLU) will be delivered one-time through a venous catheter inserted into a peripheral limb vein. A tapering course of prophylactic enteral prednisone or prednisolone will be administered for a period of at least two months.

• rAAV9.CMV.hNAGLU (Biological): Adeno-associated virus serotype 9 carrying the human NAGLU gene under the control of a CMV enhancer/promoter (rAAV9.CMV.hNAGLU) will be delivered one-time through a venous catheter inserted into a peripheral limb vein.

Primary outcomes

• Change from baseline in the Age Equivalent Developmental score (calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children Second Edition, based on developmental age) compared with Natural History Study data [24 months]
• Product safety as defined by the incidence, type and severity of treatment-related adverse events and serious adverse events [24 Months]

Secondary outcomes

• Change from baseline of central spinal fluid heparan sulfate after treatment [24 months]
• Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment [24 Months]
• Change from baseline in CSF or plasma NAGLU enzyme activity levels after treatment [24 Months]
• Change from baseline in liver and/or spleen volumes after treatment, as measured by magnetic resonance imaging [24 Months]
• Change from baseline in brain volumes after treatment, as measured by magnetic resonance imaging [24 Months]
• Change from baseline in the Cognitive Age Equivalent (Developmental Age) compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development or the Kaufman Assessment Battery for Children [24 Months]
• 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 [24 Months]
• Change from baseline Developmental Quotient after treatment compared to Natural History Study data assessed by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children. [24 Months]
• Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) Generic Core Scales total score [24 Months]
• Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) short form [24 Months]
• Determination of vector shedding analysis in plasma, saliva, urine and feces will provide preliminary data for the Environmental Risk Assessment [24 Months]

Sex: All

Inclusion Criteria:

* Confirmed diagnosis of MPSIIIB by both of the following two methods:

  * No detectable or significantly reduced NAGLU enzyme activity by plasma.
  * Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene
* Age: From Birth to 2 years or children older than 2 years with a minimum cognitive Development Quotient (DQ) of 60 or above (calculated by Bayley Scales of Infant and Toddler Development - Third Edition)

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 NAGLU gene
* Has evidence of an attenuated phenotype of MPS IIIB
* Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
* Active viral infection based on clinical observations as infections by Adenoviruses, Epstein-Barr Virus, Cytomegalovirus, Respiratory Syncytial Virus
* 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 as autoimmune diseases requiring immunosuppression, such as juvenile rheumatoid arthritis or idiopathic thrombocytopenia purpura
* Subjects with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
* Subjects 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
* Uncontrolled seizure disorder
* Any item (braces, etc.) which would exclude the subject from being able to undergo MRI according to local institutional policy
* Any other situation that precludes the subject from undergoing procedures required in this study
* Subjects with cardiomyopathy or significant congenital heart abnormalities
* The presence of significant non-MPS IlIB 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 v4.0 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
* Female participant who is pregnant or demonstrates a positive urine or serum 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

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