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Enzyme Replacement Therapy for Mucopolysaccharidosis IIID using Recombinant Human α-N-Acetylglucosamine-6-Sulfatase in Neonatal Mice

Wang, Feng and Moen, Derek R. and Sauni, Chelsee and Kan, Shih-hsin and Li, Shan and Le, Steven Q. and Lomenick, Brett and Zhang, Xiaoyi and Ekins, Sean and Singamsetty, Srikanth and Wood, Jill and Dickson, Patricia I. and Chou, Tsui-Fen (2021) Enzyme Replacement Therapy for Mucopolysaccharidosis IIID using Recombinant Human α-N-Acetylglucosamine-6-Sulfatase in Neonatal Mice. Molecular Pharmaceutics, 18 (1). pp. 214-227. ISSN 1543-8384. PMCID PMC8362844. doi:10.1021/acs.molpharmaceut.0c00831.

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There is currently no cure or effective treatment available for mucopolysaccharidosis type IIID (MPS IIID, Sanfilippo syndrome type D), a lysosomal storage disorder (LSD) caused by the deficiency of α-N-acetylglucosamine-6-sulfatase (GNS). The clinical symptoms of MPS IIID, like other subtypes of Sanfilippo syndrome, are largely localized to the central nervous system (CNS), and any treatments aiming to ameliorate or reverse the catastrophic and fatal neurologic decline caused by this disease need to be delivered across the blood–brain barrier. Here, we report a proof-of-concept enzyme replacement therapy (ERT) for MPS IIID using recombinant human α-N-acetylglucosamine-6-sulfatase (rhGNS) via intracerebroventricular (ICV) delivery in a neonatal MPS IIID mouse model. We overexpressed and purified rhGNS from CHO cells with a specific activity of 3.9 × 10⁴ units/mg protein and a maximal enzymatic activity at lysosomal pH (pH 5.6), which was stable for over one month at 4 °C in artificial cerebrospinal fluid (CSF). We demonstrated that rhGNS was taken up by MPS IIID patient fibroblasts via the mannose 6-phosphate (M6P) receptor and reduced intracellular glycosaminoglycans to normal levels. The delivery of 5 μg of rhGNS into the lateral cerebral ventricle of neonatal MPS IIID mice resulted in normalization of the enzymatic activity in brain tissues; rhGNS was found to be enriched in lysosomes in MPS IIID-treated mice relative to the control. Furthermore, a single dose of rhGNS was able to reduce the accumulated heparan sulfate and β-hexosaminidase. Our results demonstrate that rhGNS delivered into CSF is a potential therapeutic option for MPS IIID that is worthy of further development.

Item Type:Article
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URLURL TypeDescription CentralArticle
Zhang, Xiaoyi0000-0001-9732-1449
Ekins, Sean0000-0002-5691-5790
Chou, Tsui-Fen0000-0003-2410-2186
Additional Information:© 2020 American Chemical Society. Received: August 12, 2020; Revised: November 24, 2020; Accepted: November 30, 2020; Published: December 15, 2020. This study was supported by grants from the National Institutes of Health 1R41NS89061, R42NS089061, R44NS089061, and U44NS089061 to Phoenix Nest Inc. and R01NS088766 to P.I.D. S.-h.K. was supported by a T32 fellowship in the UCLA Medical Genetics Training Program (GM008243). The MPS IIID mouse model was developed by Taconic as a generous prize to Jonah’s Just Begun as part of the Rare Disease Science Challenge 2012, hosted by Assay Depot and the Rare Genomics Institute. The authors gratefully acknowledge the monthly meetings and encouragement of Dr. Emily Caporello, Dr. Jill Morris, and colleagues (NIH/NINDS). The authors appreciate Ms. Rachel Dokko and Caitlin Yumori for their initial work on this project. The authors also kindly acknowledge the support of MPSIIID families and the MPS Society. The authors would like to thank the anonymous reviewers for constructive criticism. Author Contributions. F.W., D.R.M., C.S., and S.-h.K. contributed equally to this study. The authors declare the following competing financial interest(s): C.S., D.R.M., and S.E. are former Phoenix Nest Inc. employees. S.S. and J.W. are current Phoenix Nest Inc. employees.
Funding AgencyGrant Number
NIH Predoctoral FellowshipT32 GM008243
Subject Keywords:MPS IIID, enzyme replacement therapy, GNS, CHO cells, recombinant protein production, DHFR
Issue or Number:1
PubMed Central ID:PMC8362844
Record Number:CaltechAUTHORS:20201215-141038657
Persistent URL:
Official Citation:Enzyme Replacement Therapy for Mucopolysaccharidosis IIID using Recombinant Human α-N-Acetylglucosamine-6-Sulfatase in Neonatal Mice. Feng Wang, Derek R. Moen, Chelsee Sauni, Shih-hsin Kan, Shan Li, Steven Q. Le, Brett Lomenick, Xiaoyi Zhang, Sean Ekins, Srikanth Singamsetty, Jill Wood, Patricia I. Dickson, and Tsui-Fen Chou. Molecular Pharmaceutics 2021 18 (1), 214-227; DOI: 10.1021/acs.molpharmaceut.0c00831
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:107103
Deposited By: George Porter
Deposited On:15 Dec 2020 23:09
Last Modified:10 Feb 2022 19:01

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