Procession to IND of a capsid mutated AAV8 codon optimized NAGLU vector for treatment of
Sanfilippo Syndrome type B.
Project Summary
The AAVtcm8-coNAGLU vector is able to correct the Sanfilippo Syndrome type B mouse model
to normal lysosomal storage, hearing and lifespan when injected either into the brain or into the
cisterna magna at 1.5E+11 vg/gram of brain. Additional studies in mice, dogs, and non-human
primates (NHP) indicate broad brain distribution and NAGLU expression at the same dose in
vg/g of brain weight by cisternal delivery. This project will perform the development of the
AAVtcm8-coNAGLU product to the stage of Investigational New Drug approval. Potency assays
and neutralizing antibody assays will be developed. Minimal and optimal effective dose
assessment studies will be performed along with assessment of immune response to the capsid
and NAGLU protein. Optimization of production to ensure purity and reduce empty capsids will
be performed and reproducibility of the process will be assessed for purity, potency, and
stability. Toxicology studies will be performed with the optimized product in mice and non-
human primates at half dose, target dose and 3-fold target dose to establish distribution of
vector, enzyme, and tissue toxicity. Pre-IND regulatory profiles will be submitted to and
approved by the FDA. GMP production will be performed with the optimized production methods
and assessments. Toxicology and distribution assays will be re-performed with mice and NHP
using Good Laboratory Practice to enable IND. Assays of clinical endpoints of serum and
cerebrospinal fluid NAGLU activity and heparan sulfate level will be validated. The clinical study
parameters will be determined and approved, and the IND will be submitted for FDA approval.
