FIG. 4.

Comparison of increased ARSA activity in the CNS after AAVrh.10hARSA-FLAG administration via five surgical routes in nonhuman primates. As described in Fig. 3, the right hemispheres of nonhuman primate brains were subdivided into 1-cm³ cubes and analyzed for ARSA enzymatic activity. ARSA values were corrected using paired-matched brain cube sets of PBS control nonhuman primates, and then expressed as the percent increase above the PBS (wild-type monkey) background mean corresponding to that cube set. (A) Comparison of the percentage of 1-cm³ brain cubes displaying increased ARSA activity relative to endogenous background (PBS controls) at >10, >25, and >50% levels. The percentage of cubes positive for each category was calculated on the basis of total cubes for each monkey, which varied between 77 and 97 cubes per brain. The route of vector administration is displayed along the abscissa for each group of three columns. The percentage of total brain cubes displaying an increase >10% (black columns), >25% (white columns), and >50% (gray columns) is shown for each treatment. (B–E) Comparison of ARSA activity in each coronal section for each surgical route. The mean ARSA percent increase was determined for each coronal slice by averaging the percent increase for all cubes in that section. Means are shown with SEM. Negative values indicate a value less than the PBS mean for that specific cube set. The dashed line represents the mean PBS background (0%). Coronal slices (width, 1 mm²) are displayed from the anterior to the posterior end of the NHP brains. The controls received PBS in place of AAVrh.10hARSA-FLAG via white matter administration. The surgical routes are compared with the PBS controls (baseline): (B) white matter, (C) deep gray matter with overlying white matter, (D) deep gray matter using convection-enhanced delivery, and (E) intraventricular and intraarterial. Deep gray matter routes infused into the caudate, putamen, and thalamus, whereas the white matter routes targeted the centrum semiovale white matter. Relative locations of brain substructures in coronal slices: caudate nucleus (S3–S5), putamen (S3–S4), thalamus (S4–S5), hippocampus (S4–S5), cerebellum (S5–S7).