Recombinant NAGLU-IGF2 prevents physical and neurological disease and improves survival in Sanfilippo B syndrome

Recombinant human alpha-N-acetylglucosaminidase-insulin-like growth factor-2 (rhNAGLU-IGF2) is an investigational enzyme replacement therapy for Sanfilippo B, a lysosomal storage disease. The fusion protein with IGF2 permits binding to the cation-independent mannose 6-phosphate receptor, because recombinant human NAGLU (rhNAGLU) is poorly mannose 6-phosphorylated. We previously administered rhNAGLU-IGF2 intracerebroventricularly to Sanfilippo B mice. We demonstrated therapeutic restoration of NAGLU, normalization of lysosomal storage, and improvement in markers of neurodegeneration and inflammation. Here, we studied intracerebroventricular rhNAGLU-IGF2 in murine and canine Sanfilippo B to determine potential effects on the behavioral phenotype and survival. Heparan sulfate (HS) levels in brain and heart were reduced following treatment with rhNAGLU-IGF2 or rhNAGLU. Treated mice showed improvement in disease markers such as beta-hexosaminidase, CD68, and LAMP1. We found a more normal number of stretch attend postures, a fear pose, in mice treated with either rhNAGLU or rhNAGLU-IGF2 vs vehicle-treated Sanfilippo B mice on elevated plus maze testing (p<0.001). We found a more normal dark/light activity pattern in Sanfilippo B mice treated with rhNAGLU-IGF2 compared to vehicle-treated Sanfilippo B mice (p=0.025). We found a 61% increase in survival in Sanfilippo B mice treated with rhNAGLU-IGF2 (mean 53d, median 48d) compared to vehicle-treated Sanfilippo B mice (mean 33d, median 37d; p<0.001). In canine Sanfilippo B, we found that rhNAGLU-IGF2 administered into cerebrospinal fluid normalized heparan sulfate and beta-hexosaminidase activity in gray and white matter brain regions. Proteomics analysis of cerebral cortex showed restoration of protein concentrations in pathways relevant to cognitive function, synapse, and the lysosome. Treatment with rhNAGLU-IGF2 may improve the phenotype of Sanfilippo B disease.