title: Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB.
abstract: Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disease characterized by profound intellectual disability, dementia, and a lifespan of about two decades. The cause is mutation in the gene encoding α-N-acetylglucosaminidase (NAGLU), deficiency of NAGLU, and accumulation of heparan sulfate. Impediments to enzyme replacement therapy are the absence of mannose 6-phosphate on recombinant human NAGLU and the blood-brain barrier. To overcome the first impediment, a fusion protein of recombinant NAGLU and a fragment of insulin-like growth factor II (IGFII) was prepared for endocytosis by the mannose 6-phosphate/IGFII receptor. To bypass the blood-brain barrier, the fusion protein ("enzyme") in artificial cerebrospinal fluid ("vehicle") was administered intracerebroventricularly to the brain of adult MPS IIIB mice, four times over 2 wk. The brains were analyzed 1-28 d later and compared with brains of MPS IIIB mice that received vehicle alone or control (heterozygous) mice that received vehicle. There was marked uptake of the administered enzyme in many parts of the brain, where it persisted with a half-life of approximately 10 d. Heparan sulfate, and especially disease-specific heparan sulfate, was reduced to control level. A number of secondary accumulations in neurons [β-hexosaminidase, LAMP1(lysosome-associated membrane protein 1), SCMAS (subunit c of mitochondrial ATP synthase), glypican 5, β-amyloid, P-tau] were reduced almost to control level. CD68, a microglial protein, was reduced halfway. A large amount of enzyme also appeared in liver cells, where it reduced heparan sulfate and β-hexosaminidase accumulation to control levels. These results suggest the feasibility of enzyme replacement therapy for MPS IIIB.
authors.affiliation: Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502;
authors.forename: Shih-Hsin
authors.initials: SH
authors.lastname: Kan
authors.affiliation: Research and Drug Discovery and eneufeld@mednet.ucla.edu MAoyagi-scharber@bmrn.com pdickson@labiomed.org.
authors.forename: Mika
authors.initials: M
authors.lastname: Aoyagi-Scharber
authors.affiliation: Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502;
authors.forename: Steven Q
authors.initials: SQ
authors.lastname: Le
authors.affiliation: Research and Drug Discovery and.
authors.forename: Jon
authors.initials: J
authors.lastname: Vincelette
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ohmi
authors.affiliation: Research and Drug Discovery and.
authors.forename: Sherry
authors.initials: S
authors.lastname: Bullens
authors.affiliation: Analytical Chemistry, BioMarin Pharmaceutical, Inc., Novato, CA 94949; and.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Wendt
authors.affiliation: Research and Drug Discovery and.
authors.forename: Terri M
authors.initials: TM
authors.lastname: Christianson
authors.affiliation: Research and Drug Discovery and.
authors.forename: Pascale M N
authors.initials: PM
authors.lastname: Tiger
authors.affiliation: Research and Drug Discovery and.
authors.forename: Jillian R
authors.initials: JR
authors.lastname: Brown
authors.affiliation: Research and Drug Discovery and.
authors.forename: Roger
authors.initials: R
authors.lastname: Lawrence
authors.affiliation: Research and Drug Discovery and.
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Yip
authors.affiliation: Research and Drug Discovery and.
authors.forename: John
authors.initials: J
authors.lastname: Holtzinger
authors.affiliation: Research and Drug Discovery and.
authors.forename: Anil
authors.initials: A
authors.lastname: Bagri
authors.affiliation: Research and Drug Discovery and.
authors.forename: Danielle
authors.initials: D
authors.lastname: Crippen-Harmon
authors.affiliation: Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502;
authors.forename: Kristen N
authors.initials: KN
authors.lastname: Vondrak
authors.affiliation: Analytical Chemistry, BioMarin Pharmaceutical, Inc., Novato, CA 94949; and.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Analytical Chemistry, BioMarin Pharmaceutical, Inc., Novato, CA 94949; and.
authors.forename: Chuck M
authors.initials: CM
authors.lastname: Hague
authors.affiliation: Research and Drug Discovery and.
authors.forename: Josh C
authors.initials: JC
authors.lastname: Woloszynek
authors.affiliation: Research and Drug Discovery and.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Cheung
authors.affiliation: Research and Drug Discovery and.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Webster
authors.affiliation: Research and Drug Discovery and.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Adintori
authors.affiliation: Research and Drug Discovery and.
authors.forename: Melanie J
authors.initials: MJ
authors.lastname: Lo
authors.affiliation: Research and Drug Discovery and.
authors.forename: Wesley
authors.initials: W
authors.lastname: Wong
authors.affiliation: Research and Drug Discovery and.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fitzpatrick
authors.affiliation: Research and Drug Discovery and.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: LeBowitz
authors.affiliation: Research and Drug Discovery and.
authors.forename: Brett E
authors.initials: BE
authors.lastname: Crawford
authors.affiliation: Research and Drug Discovery and.
authors.forename: Stuart
authors.initials: S
authors.lastname: Bunting
authors.affiliation: Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502; eneufeld@mednet.ucla.edu MAoyagi-scharber@bmrn.com pdickson@labiomed.org.
authors.forename: Patricia I
authors.initials: PI
authors.lastname: Dickson
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 eneufeld@mednet.ucla.edu MAoyagi-scharber@bmrn.com pdickson@labiomed.org.
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Neufeld
mesh_terms: D000118:Acetylglucosaminidase / Q000627:therapeutic use*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D016503:Drug Delivery Systems; D004705:Endocytosis; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D007276:Injections, Intraventricular; D007335:Insulin-Like Growth Factor II / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D051379:Mice; D009084:Mucopolysaccharidosis III / Q000188:drug therapy* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000627:therapeutic use*; D001619:beta-N-Acetylhexosaminidases / Q000378:metabolism; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000118:Acetylglucosaminidase; D015415:Biomarkers; D006497:Heparan Sulfate; D007335:Insulin-Like Growth Factor II; D051907:Lysosomal Membrane Proteins; D011993:Recombinant Fusion Proteins; D001619:beta-N-Acetylhexosaminidases; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C033079:alpha-N-acetyl-D-glucosaminidase