Single Injection of rAAV9-CMV-hNAGLUop Gene for Patients With Mucopolysaccharidosis (MPS) IIIB

This is a dose escalation study where one infusion of rAAV9-CMV-hNAGLUop will be administered to patients with Sanfilippo Disease (MPS III).

Patients will go through an Informed Consent process and eligibility assessed by reviewing patient medical history and laboratory values.

Eligible patients will receive the infusion of rAAV9-CMV-hNAGLUop followed by an inpatient stay in the hospital for at least one night. Over the next 30 days, participants and their caregiver(s) will stay in a home near the hospital to facilitate visits back to the hospital. Participants will have laboratory samples collected at a lab near their home at days 45 and 75. Participants will come back to Washington University St. Louis at Day 60, Day 90, Day 120, Day 180, Month 12, Month 18 and Month 12 to have laboratory tests and other assessments, including ECG, motor skills assessments, gait test, questionnaires, and evaluation by the PI completed.

Inclusion criteria

• Age >6 months
• Confirmed diagnosis of MPS IIIB based upon meeting the following conditions:

• No detectable or significantly reduced N-acetyl-α-glucosaminidase (NAGLU) enzyme activity by leukocyte assay from CLIA-certified laboratory
• Two variants classified as pathogenic or likely pathogenic in NAGLU on clinical laboratory testing. Variants will be interpreted using the American College of Medical Genetics guidelines for the interpretation of sequence variants and testing must be performed by a CLIA-certified laboratory.
• Clinical history of developmental delays defined as a score of >1 standard deviation below the mean in at least one domain of neuropsychological function (language, memory, non-verbal ability), OR documented historical evidence of a decline of >1 standard deviation on sequential testing, OR a score between 0.75 and 1 standard deviation below the mean and the cognitive defect affects daily performance.

Exclusion criteria

• Receipt of an investigational drug or procedure within 30 days of signing consent.
• A condition, medical or other, that prevents participation in the study, including severe auditory or visual impairment, significant lumbar pathology, lumbar catheter, airway or other factors that preclude the use of general anesthesia, bleeding diathesis, or recent major surgery within 6 weeks of screening that would preclude the patient's ability to participate.
• Active viral infection (includes HIV, or serology consistent with active hepatitis A, B or C infection)
• Clinically significant abnormal hematology within 1 month of infusion (complete blood count with differential), blood chemistry (including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), bilirubin, creatinine, and CRP), coagulability labs (international normalized ration (INR), prothrombin time (PT), activated partial thromboplastin time (aPTT). An abnormal laboratory value will be based on clinical laboratory reference ranges and Investigator's clinical judgment and will be deemed clinically significant if either of the following are met at baseline:

• The abnormality suggests a disease and/or organ toxicity beyond what is expected in Sanfilippo syndrome and/or beyond what would be considered safe for viral vector administration in the opinion of the investigator, or
• The abnormality is of a degree that requires additional active management, such as close observation, change in medication, or further diagnostic investigation.
• Concomitant febrile illness or requirement for chronic drug treatment that in the opinion of the Investigator creates unnecessary risks for gene transfer.
• Anti-AAV9 antibody titers > 1:100 as determined by binding ELISA assay
• Participants who, in the opinion of the Investigator, are unable to comply with the protocol. Examples of inability to comply include unwillingness to travel to the study site, suspected noncompliance with study procedures, behavior that jeopardizes the safety or security of the data or study staff, and other causes of inability to comply.
• Uncontrolled seizure disorder. Participants who are stable on anticonvulsive medications may be included.
• Implanted metal objects or pacemakers that preclude MRI
• Patients with severe cardiomyopathy or significant congenital heart abnormalities
• The presence of significant non-MPS IIIB related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
• Patients with signs, symptoms, or treatment of infection or administration of vaccines in the 6 weeks prior to study enrollment