Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA

• Increase in CSF and blood leukocyte SGSH enzyme activity levels at 6 and/or 12 months [ Time Frame: 12 months ]
• Reduced liver and spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI) [ Time Frame: 12 months ]
• Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months, as assessed by parent report using the Vineland Adaptive Behavior Scale [ Time Frame: 12 months ]
• Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Leiter International Performance Scale and the Mullen Scales of Early Learning [ Time Frame: 12 months ]
• Reduction of urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment [ Time Frame: 12 months ]

• Experimental: Cohort 1 Low Dose

  Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

  • Cohort 1 (Low Dose): 5 X 10^12 vg/kg (n=3 subjects)

  Intervention: Biological: scAAV9.U1a.hSGSH
• Experimental: Cohort 2 High Dose

  Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

  • Cohort 2 (High Dose): 1 X 10^13 vg/kg (n=3-6 subjects)

  Intervention: Biological: scAAV9.U1a.hSGSH

Inclusion Criteria:

• Age 2 years old or greater
• Confirmed diagnosis of MPS IIIA by either of two methods:
• No detectable or significantly reduced* SGSH enzyme activity by leukocyte or fibroblast assay.
• Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene
• Clinical history or examination features of neurologic dysfunction

Exclusion Criteria:

• Inability to participate in the clinical evaluation as determined by PI
• Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
• Inability to be safely sedated in the opinion of the clinical anesthesiologist
• 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
• Subjects with anti-AAV9 antibody titers ≥ 1:50 as determined by ELISA binding immunoassay
• Serology consistent with exposure to HIV, or serology consistent with active hepatitis A, 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, due to the requirement for multiple MRI examinations as part of the study protocol. Subjects who are stable on anticonvulsive medications may be included
• Any item (braces, etc.) which would exclude the patient from being able to undergo MRI according to local institutional policy
• Any item (braces, etc.) which would exclude the patient from being able to undergo MRI according to local institutional policy
• Patients 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, clinically significant laboratory values based upon normal values in the Nationwide Children's Hospital Laboratory as listed in Table 1 of the protocol.

  • Due to the nature of enzyme activity testing, normal ranges and reported units vary from lab to lab. Many laboratories utilize control samples rather than normal ranges, to account for the influence of small day-to-day fluctuations in the laboratory environment.
  • For the purposes of invitation to a screening visit, we will accept "significantly reduced" results as those interpreted as such by any clinical laboratory approved to perform this diagnostic test.

For uniformity of data for analysis, and confirmation of accurate diagnosis before gene transfer, subjects who consent to complete the screening visit will have their blood drawn for confirmatory enzyme activity level to be performed by Greenwood Genetics Center Biochemical Laboratory. Subjects must have an enzyme activity level considered to be in the affected range by Greenwood Genetic Center Biochemical Laboratory to proceed within the study.