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

Abstract

AbstractRecombinant human alpha-N-acetylglucosaminidase-insulin-like growth factor-2 (rhNAGLU-IGF2) is an investigational enzyme replacement therapy for Sanfilippo B, a lysosomal storage disease. Because recombinant human NAGLU (rhNAGLU) is poorly mannose 6-phosphorylated, we generated a fusion protein of NAGLU with IGF2 to permit its binding to the cation-independent mannose 6-phosphate receptor. We previously administered rhNAGLU-IGF2 intracerebroventricularly to Sanfilippo B mice, and demonstrated therapeutic restoration of NAGLU, normalization of lysosomal storage, and improvement in markers of neurodegeneration and inflammation. Here, we studied intracerebroventricular rhNAGLU-IGF2 delivery in both murine and canine Sanfilippo B to determine potential effects on their behavioral phenotypes and survival. Treated mice showed improvement in disease markers such as heparan sulfate glycosaminoglycans, beta-hexosaminidase, microglial activation, and lysosomal-associated membrane protein-1. Sanfilippo B mice treated with rhNAGLU-IGF2 displayed partial normalization of their stretch attend postures, a defined fear pose in mice (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 also found a 61% increase in survival in Sanfilippo B mice treated with rhNAGLU-IGF2 (mean 53w, median 48w) compared to vehicle-treated Sanfilippo B mice (mean 33w, median 37w; p<0.001). In canine Sanfilippo B, we found that rhNAGLU-IGF2 administered into cerebrospinal fluid normalized HS and beta-hexosaminidase activity in gray and white matter brain regions. Proteomic analysis of cerebral cortex showed restoration of protein expression levels in pathways relevant to cognitive function, synapse, and the lysosome. These data suggest that treatment with rhNAGLU-IGF2 may improve the phenotype of Sanfilippo B disease.