Translational studies of intravenous and intracerebroventricular routes of administration for CNS cellular biodistribution for BMN 250, an enzyme replacement therapy for the treatment of Sanfilippo type B

Drug Deliv Transl Res. 2020 Apr;10(2):425-439. doi: 10.1007/s13346-019-00683-6.


BMN 250 is being developed as enzyme replacement therapy for Sanfilippo type B, a primarily neurological rare disease, in which patients have deficient lysosomal alpha-N-acetylglucosaminidase (NAGLU) enzyme activity. BMN 250 is taken up in target cells by the cation-independent mannose 6-phosphate receptor (CI-MPR, insulin-like growth factor 2 receptor), which then facilitates transit to the lysosome. BMN 250 is dosed directly into the central nervous system via the intracerebroventricular (ICV) route, and the objective of this work was to compare systemic intravenous (IV) and ICV delivery of BMN 250 to confirm the value of ICV dosing. We first assess the ability of enzyme to cross a potentially compromised blood-brain barrier in the Naglu-/- mouse model and then assess the potential for CI-MPR to be employed for receptor-mediated transport across the blood-brain barrier. In wild-type and Naglu-/- mice, CI-MPR expression in brain vasculature is high during the neonatal period but virtually absent by adolescence. In contrast, CI-MPR remains expressed through adolescence in non-affected non-human primate and human brain vasculature. Combined results from IV administration of BMN 250 in Naglu-/- mice and IV and ICV administration in healthy juvenile non-human primates suggest a limitation to therapeutic benefit from IV administration because enzyme distribution is restricted to brain vascular endothelial cells: enzyme does not reach target neuronal cells following IV administration, and pharmacological response following IV administration is likely restricted to clearance of substrate in endothelial cells. In contrast, ICV administration enables central nervous system enzyme replacement with biodistribution to target cells.

Keywords: Alpha-N-acetylglucosaminidase; Enzyme replacement therapy; Intracerebroventricular delivery; Lysosomal storage diseases; Mucopolysaccharidosis type III; Sanfilippo type B.

Publication types

  • Comparative Study

MeSH terms

  • Acetylglucosaminidase / administration & dosage*
  • Acetylglucosaminidase / genetics*
  • Acetylglucosaminidase / therapeutic use
  • Administration, Intravenous
  • Animals
  • Blood-Brain Barrier / chemistry*
  • Disease Models, Animal
  • Enzyme Replacement Therapy
  • Female
  • Infusions, Intraventricular
  • Insulin-Like Growth Factor II / administration & dosage*
  • Insulin-Like Growth Factor II / therapeutic use
  • Male
  • Mice
  • Mice, Transgenic
  • Mucopolysaccharidosis III / drug therapy*
  • Mucopolysaccharidosis III / genetics
  • Primates
  • Receptor, IGF Type 2 / metabolism*
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / therapeutic use
  • Translational Research, Biomedical


  • BMN 250
  • Receptor, IGF Type 2
  • Recombinant Fusion Proteins
  • Insulin-Like Growth Factor II
  • alpha-N-acetyl-D-glucosaminidase
  • Acetylglucosaminidase