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Recombinant NAGLU-IGF2 prevents physical and neurological disease and improves survival in Sanfilippo B syndrome

Le, Steven Q. and Kan, Shih-hsin and Nuñez, Marie and Dearborn, Joshua T. and Wang, Feng and Li, Shan and Snella, Liz and Jens, Jackie K. and Valentine, Bethann N. and Nelvagal, Hemanth R. and Sorensen, Alexander and Cooper, Jonathan D. and Chou, Tsui-Fen and Ellinwood, N. Matthew and Smith, Jodi D. and Sands, Mark S. and Dickson, Patricia I. (2021) Recombinant NAGLU-IGF2 prevents physical and neurological disease and improves survival in Sanfilippo B syndrome. . (Unpublished)

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Recombinant human alpha-N-acetylglucosaminidase-insulin-like growth factor-2 (rhNAGLU-IGF2) is an investigational enzyme replacement therapy for Sanfilippo B, a lysosomal storage disease. Because recombinant human NAGLU (rhNAGLU) is poorly mannose 6-phosphorylated, we generated a fusion protein of NAGLU with IGF2 to permit its binding to the cation-independent mannose 6-phosphate receptor. We previously administered rhNAGLU-IGF2 intracerebroventricularly to Sanfilippo B mice, and demonstrated therapeutic restoration of NAGLU, normalization of lysosomal storage, and improvement in markers of neurodegeneration and inflammation. Here, we studied intracerebroventricular rhNAGLU-IGF2 delivery in both murine and canine Sanfilippo B to determine potential effects on their behavioral phenotypes and survival. Treated mice showed improvement in disease markers such as heparan sulfate glycosaminoglycans, beta-hexosaminidase, microglial activation, and lysosomal-associated membrane protein-1. Sanfilippo B mice treated with rhNAGLU-IGF2 displayed partial normalization of their stretch attend postures, a defined fear pose in mice (p<0.001). We found a more normal dark/light activity pattern in Sanfilippo B mice treated with rhNAGLU-IGF2 compared to vehicle-treated Sanfilippo B mice (p=0.025). We also found a 61% increase in survival in Sanfilippo B mice treated with rhNAGLU-IGF2 (mean 53w, median 48w) compared to vehicle-treated Sanfilippo B mice (mean 33w, median 37w; p<0.001). In canine Sanfilippo B, we found that rhNAGLU-IGF2 administered into cerebrospinal fluid normalized HS and beta-hexosaminidase activity in gray and white matter brain regions. Proteomic analysis of cerebral cortex showed restoration of protein expression levels in pathways relevant to cognitive function, synapse, and the lysosome. These data suggest that treatment with rhNAGLU-IGF2 may improve the phenotype of Sanfilippo B disease.

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Dearborn, Joshua T.0000-0003-0335-1087
Li, Shan0000-0002-0829-1821
Snella, Liz0000-0003-1482-2876
Nelvagal, Hemanth R.0000-0003-2407-4517
Cooper, Jonathan D.0000-0003-1339-4750
Chou, Tsui-Fen0000-0003-2410-2186
Ellinwood, N. Matthew0000-0002-1701-5052
Smith, Jodi D.0000-0001-7952-8024
Sands, Mark S.0000-0002-5559-0832
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. Version 1 - August 8, 2021; Version 2 - September 15, 2021; Version 3 - September 16, 2021. P.I.D., J.T.D., M.S.S., and J.D.C. designed experiments and prepared the manuscript. S.Q.L., S.-h.K., M.N., and J.T.D. performed mouse experiments. S.Q.L, A.S., H.R.N., and J.D.C. performed quantitative immunofluorescence. L.S., B.N.V., N.M.E., J.J., and J.D.S. performed canine experiments. F.W., S.L, S.Q.L., and T.F.C. performed enzyme assays and/or proteomics on canine tissues. We gratefully acknowledge the assistance and support of Soila Sukipolvi, Irina Zhuravka, George Lopez, Ling Wang, Valentina Sanguez, and Catalina Guerra. BioMarin Pharmaceutical provided vehicle, rhNAGLU, and rhNAGLU-IGF2. BioMarin provided HS measurement of mouse brain and heart tissues. We gratefully acknowledge Roger Lawrence and Brett Crawford for their specific assistance with these assays. Research was supported by R01 NS088766 to P.I.D. The Washington University Animal Behavioral services are supported by the Eunice Kennedy Shriver National Institute Of Child Health & Human Development of the National Institutes of Health under Award Number P50 HD103525 to the Intellectual and Developmental Disabilities Research Center at Washington University. A traineeship from 5T32 GM8243-28 (to S.-h.K.) The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The UCLA Behavioral Testing Core is supported by the UCLA Bioscience Core Funding Initiative. Immunofluorescence imaging was performed in part through the use of Washington University Center for Cellular Imaging (WUCCI) supported by Washington University School of Medicine, The Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (CDI-CORE-2015-505 and CDI-CORE-2019-813) and the Foundation for Barnes-Jewish Hospital (3770 and 4642). Conflicts of Interest: BioMarin Pharmaceutical Inc provided research materials for this study. Dr. Dickson receives research support from Genzyme and research materials from M6P Therapeutics.
Funding AgencyGrant Number
NIHR01 NS088766
NIHP50 HD103525
NIH Predoctoral Fellowship5T32 GM8243-28
Washington UniversityUNSPECIFIED
Children’s Discovery InstituteUNSPECIFIED
St. Louis Children’s Hospital FoundationCDI-CORE-2015-505
St. Louis Children’s Hospital FoundationCDI-CORE-2019-813
Foundation for Barnes-Jewish Hospital3770
Foundation for Barnes-Jewish Hospital4642
Subject Keywords:mucopolysaccharidosis, enzyme replacement therapy, glycosaminoglycan, proteomics, lysosomal storage disease
Record Number:CaltechAUTHORS:20210810-163528980
Persistent URL:
Official Citation:Recombinant NAGLU-IGF2 prevents physical and neurological disease and improves survival in Sanfilippo B syndrome. Steven Q. Le, Shih-hsin Kan, Marie Nuñez, Joshua T. Dearborn, Feng Wang, Shan LI, Liz Snella, Jackie K Jens, Bethann N Valentine, Hemanth R Nelvagal, Alexander Sorensen, Jonathan D Cooper, Tsui-Fen Chou, N Matthew Ellinwood, Jodi D Smith, Mark S Sands, Patricia Dickson. bioRxiv 2021.08.06.455469; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:110190
Deposited By: Tony Diaz
Deposited On:11 Aug 2021 21:47
Last Modified:16 Nov 2021 19:39

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