Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice

被引：27

作者：

Aoyagi-Scharber, Mika ^{[1
]}

Crippen-Harmon, Danielle ^{[1
]}

Lawrence, Roger ^{[1
]}

Vincelette, Jon ^{[1
]}

Yogalingam, Gouri ^{[1
]}

Prill, Heather ^{[1
]}

Yip, Bryan K. ^{[1
]}

Baridon, Brian ^{[1
]}

Vitelli, Catherine ^{[1
]}

Lee, Amanda ^{[1
]}

Gorostiza, Olivia ^{[1
]}

Adintori, Evan G. ^{[1
]}

Minto, Wesley C. ^{[1
]}

Van Vleet, Jeremy L. ^{[1
]}

Yates, Bridget ^{[1
]}

Rigney, Sara ^{[1
]}

Christianson, Terri M. ^{[1
]}

Tiger, Pascale M. N. ^{[1
]}

Lo, Melanie J. ^{[1
]}

Holtzinger, John ^{[1
]}

Fitzpatrick, Paul A. ^{[1
]}

LeBowitz, Jonathan H. ^{[1
]}

Bullens, Sherry ^{[1
]}

Crawford, Brett E. ^{[1
]}

Bunting, Stuart ^{[1
]}

机构：

[1] BioMarin Pharmaceut Inc, Res, 105 Digital Dr, Novato, CA 94949 USA

来源：

MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT | 2017年 / 6卷

关键词：

ALPHA-N-ACETYLGLUCOSAMINIDASE; MUCOPOLYSACCHARIDOSIS TYPE IIIB; ENZYME REPLACEMENT THERAPY; BLOOD-BRAIN-BARRIER; MOUSE MODEL; CEREBROSPINAL-FLUID; LYSOSOMAL STORAGE; FUSION PROTEIN; NEUROLOGICAL DISEASE; GENE-THERAPY;

D O I：

10.1016/j.omtm.2017.05.009

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of alpha-N-acetylglucosaminidase (NAGLU), required for lysosomal degradation of heparan sulfate (HS), is a pediatric neurodegenerative disorder with no approved treatment. Intracerebroventricular (ICV) delivery of a modified recombinant NAGLU, consisting of human NAGLU fused with insulin-like growth factor 2 (IGF2) for enhanced lysosomal targeting, was previously shown to result in marked enzyme uptake and clearance of HS storage in the Naglu(-/-) mouse brain. To further evaluate regional, cell type-specific, and dose-dependent biodistribution of NAGLUIGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu(-/-) mice were treated with 1-100 mu g ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 mu g doses) resulted in above-normal NAGLU activity levels, broad biodistribution, and uptake in all cell types, with NAGLU predominantly localized to neurons in the Naglu(-/-) mouse brain. This led to complete clearance of disease-specific HS and reduction of secondary lysosomal defects and neuropathology across various brain regions lasting for at least 28 days after the last dose. The substantial brain uptake of NAGLU attainable by this highest ICV dosage was required for nearly complete attenuation of disease-driven storage accumulations and neuropathology throughout the Naglu(-/-) mouse brain.

引用

页码：43 / 53

页数：11

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