Intravenous SBC-103, a recombinant human alpha-N-acetylglucosaminidase reduces CNS heparan sulfate content in a mucopolysaccharidosis type IIIB mouse model

Rutkowski, Joseph V.; Harbert, Kari; Xu, Hao; Hu, Wei; Renninger, Matthew L.; Leavitt, Mark C.; Chen, Qinming; Rojas-Caro, Sandra; Quinn, Anthony G.

doi:10.1016/j.ymgme.2013.12.222

Cited by 4 publications

(2 citation statements)

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“…It is composed of capillary endothelial cells, astrocyte end-feet, capillary basement membrane, and pericytes within the basement membrane [5]. Receptor-mediated pathways exist for transit across the BBB, including one proposed to be mediated by CI-MPR [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

“…CI-MPR has been indirectly shown to facilitate trans-BBB transport of β-glucoronidase and sulfamidase in neonatal, but not adult wild-type (WT) mice, in a M6P-dependent manner [7,8]. Similarly, a recombinant human NAGLU with enhanced mannose 6-phosphorylation has been proposed to provide sufficient brain distribution for therapeutic benefit when dosed systemically [6]. It has also been proposed that compromised BBB in Naglu −/− mice resulting from disease-specific pathology may allow for brain distribution by systemically delivered of ERT [9].…”

Section: Introductionmentioning

confidence: 99%

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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

Grover

Crippen-Harmon

Nave

et al. 2020

Drug Deliv. and Transl. Res.

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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.

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