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