Gene Transfer Clinical Trial for Mucopolysaccharidosis (MPS) IIIB

Phase I/II Gene Transfer Clinical Trial of rAAV9.CMV.hNAGLU for Mucopolysaccharidosis (MPS) IIIB

Open-label, dose-escalation clinical trial of rAAV9.CMV.hNAGLU injected intravenously through a peripheral limb vein

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.

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