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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2017-09-01
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| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050117300748 |
| _version_ | 1818055768973246464 |
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| author | Mika Aoyagi-Scharber Danielle Crippen-Harmon Roger Lawrence Jon Vincelette Gouri Yogalingam Heather Prill Bryan K. Yip Brian Baridon Catherine Vitelli Amanda Lee Olivia Gorostiza Evan G. Adintori Wesley C. Minto Jeremy L. Van Vleet Bridget Yates Sara Rigney Terri M. Christianson Pascale M.N. Tiger Melanie J. Lo John Holtzinger Paul A. Fitzpatrick Jonathan H. LeBowitz Sherry Bullens Brett E. Crawford Stuart Bunting |
| author_facet | Mika Aoyagi-Scharber Danielle Crippen-Harmon Roger Lawrence Jon Vincelette Gouri Yogalingam Heather Prill Bryan K. Yip Brian Baridon Catherine Vitelli Amanda Lee Olivia Gorostiza Evan G. Adintori Wesley C. Minto Jeremy L. Van Vleet Bridget Yates Sara Rigney Terri M. Christianson Pascale M.N. Tiger Melanie J. Lo John Holtzinger Paul A. Fitzpatrick Jonathan H. LeBowitz Sherry Bullens Brett E. Crawford Stuart Bunting |
| author_sort | Mika Aoyagi-Scharber |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-10T12:18:12Z |
| format | Article |
| id | doaj.art-391415b4d80b4db49263e27fbcc2640a |
| institution | Directory Open Access Journal |
| issn | 2329-0501 |
| language | English |
| last_indexed | 2024-12-10T12:18:12Z |
| publishDate | 2017-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj.art-391415b4d80b4db49263e27fbcc2640a2022-12-22T01:49:10ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012017-09-016C435310.1016/j.omtm.2017.05.009Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B MiceMika Aoyagi-Scharber0Danielle Crippen-Harmon1Roger Lawrence2Jon Vincelette3Gouri Yogalingam4Heather Prill5Bryan K. Yip6Brian Baridon7Catherine Vitelli8Amanda Lee9Olivia Gorostiza10Evan G. Adintori11Wesley C. Minto12Jeremy L. Van Vleet13Bridget Yates14Sara Rigney15Terri M. Christianson16Pascale M.N. Tiger17Melanie J. Lo18John Holtzinger19Paul A. Fitzpatrick20Jonathan H. LeBowitz21Sherry Bullens22Brett E. Crawford23Stuart Bunting24Research, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USAResearch, BioMarin Pharmaceutical Inc., 105 Digital Drive, Novato, CA 94949, USASanfilippo 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.http://www.sciencedirect.com/science/article/pii/S2329050117300748lysosomal storage disordermucopolysaccharidosis IIIBMPS IIIBSanfilippo Benzyme replacement therapyintracerebroventricular deliveryglycosaminoglycanneurodegenerationmental retardation |
| spellingShingle | Mika Aoyagi-Scharber Danielle Crippen-Harmon Roger Lawrence Jon Vincelette Gouri Yogalingam Heather Prill Bryan K. Yip Brian Baridon Catherine Vitelli Amanda Lee Olivia Gorostiza Evan G. Adintori Wesley C. Minto Jeremy L. Van Vleet Bridget Yates Sara Rigney Terri M. Christianson Pascale M.N. Tiger Melanie J. Lo John Holtzinger Paul A. Fitzpatrick Jonathan H. LeBowitz Sherry Bullens Brett E. Crawford Stuart Bunting Clearance of Heparan Sulfate and Attenuation of CNS Pathology by Intracerebroventricular BMN 250 in Sanfilippo Type B Mice Molecular Therapy: Methods & Clinical Development lysosomal storage disorder mucopolysaccharidosis IIIB MPS IIIB Sanfilippo B enzyme replacement therapy intracerebroventricular delivery glycosaminoglycan neurodegeneration mental retardation |
| 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 | lysosomal storage disorder mucopolysaccharidosis IIIB MPS IIIB Sanfilippo B enzyme replacement therapy intracerebroventricular delivery glycosaminoglycan neurodegeneration mental retardation |
| url | http://www.sciencedirect.com/science/article/pii/S2329050117300748 |
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