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Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice
Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society of Gene & Cell Therapy
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480280/ https://www.ncbi.nlm.nih.gov/pubmed/28664165 http://dx.doi.org/10.1016/j.omtm.2017.05.009 |
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author | Aoyagi-Scharber, Mika Crippen-Harmon, Danielle Lawrence, Roger Vincelette, Jon Yogalingam, Gouri Prill, Heather Yip, Bryan K. Baridon, Brian Vitelli, Catherine Lee, Amanda Gorostiza, Olivia Adintori, Evan G. Minto, Wesley C. Van Vleet, Jeremy L. Yates, Bridget Rigney, Sara Christianson, Terri M. Tiger, Pascale M.N. Lo, Melanie J. Holtzinger, John Fitzpatrick, Paul A. LeBowitz, Jonathan H. Bullens, Sherry Crawford, Brett E. Bunting, Stuart |
author_facet | Aoyagi-Scharber, Mika Crippen-Harmon, Danielle Lawrence, Roger Vincelette, Jon Yogalingam, Gouri Prill, Heather Yip, Bryan K. Baridon, Brian Vitelli, Catherine Lee, Amanda Gorostiza, Olivia Adintori, Evan G. Minto, Wesley C. Van Vleet, Jeremy L. Yates, Bridget Rigney, Sara Christianson, Terri M. Tiger, Pascale M.N. Lo, Melanie J. Holtzinger, John Fitzpatrick, Paul A. LeBowitz, Jonathan H. Bullens, Sherry Crawford, Brett E. Bunting, Stuart |
author_sort | Aoyagi-Scharber, Mika |
collection | PubMed |
description | Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-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 NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu(−/−) mice were treated with 1–100 μg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 μg 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. |
format | Online Article Text |
id | pubmed-5480280 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | American Society of Gene & Cell Therapy |
record_format | MEDLINE/PubMed |
spelling | pubmed-54802802017-06-29 Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice Aoyagi-Scharber, Mika Crippen-Harmon, Danielle Lawrence, Roger Vincelette, Jon Yogalingam, Gouri Prill, Heather Yip, Bryan K. Baridon, Brian Vitelli, Catherine Lee, Amanda Gorostiza, Olivia Adintori, Evan G. Minto, Wesley C. Van Vleet, Jeremy L. Yates, Bridget Rigney, Sara Christianson, Terri M. Tiger, Pascale M.N. Lo, Melanie J. Holtzinger, John Fitzpatrick, Paul A. LeBowitz, Jonathan H. Bullens, Sherry Crawford, Brett E. Bunting, Stuart Mol Ther Methods Clin Dev Original Article Sanfilippo syndrome type B (mucopolysaccharidosis IIIB), caused by inherited deficiency of α-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 NAGLU-IGF2 (BMN 250) and its effects on biochemical and histological pathology, Naglu(−/−) mice were treated with 1–100 μg ICV doses (four times over 2 weeks). 1 day after the last dose, BMN 250 (100 μg 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. American Society of Gene & Cell Therapy 2017-06-06 /pmc/articles/PMC5480280/ /pubmed/28664165 http://dx.doi.org/10.1016/j.omtm.2017.05.009 Text en © 2017 BioMarin Pharmaceutical Inc. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Aoyagi-Scharber, Mika Crippen-Harmon, Danielle Lawrence, Roger Vincelette, Jon Yogalingam, Gouri Prill, Heather Yip, Bryan K. Baridon, Brian Vitelli, Catherine Lee, Amanda Gorostiza, Olivia Adintori, Evan G. Minto, Wesley C. Van Vleet, Jeremy L. Yates, Bridget Rigney, Sara Christianson, Terri M. Tiger, Pascale M.N. Lo, Melanie J. Holtzinger, John Fitzpatrick, Paul A. LeBowitz, Jonathan H. Bullens, Sherry Crawford, Brett E. Bunting, Stuart Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice |
title | Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice |
title_full | Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice |
title_fullStr | Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice |
title_full_unstemmed | Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice |
title_short | Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice |
title_sort | clearance of heparan sulfate and attenuation of cns pathology by intracerebroventricular bmn 250 in sanfilippo type b mice |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5480280/ https://www.ncbi.nlm.nih.gov/pubmed/28664165 http://dx.doi.org/10.1016/j.omtm.2017.05.009 |
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