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Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14870-5. doi: 10.1073/pnas.1416660111. Epub 2014 Sep 29.

Delivery of an enzyme-IGFII fusion protein to the mouse brain is therapeutic for mucopolysaccharidosis type IIIB.

Author information

1
Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA 90502;
2
Research and Drug Discovery and eneufeld@mednet.ucla.edu MAoyagi-scharber@bmrn.com pdickson@labiomed.org.
3
Research and Drug Discovery and.
4
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
5
Analytical Chemistry, BioMarin Pharmaceutical, Inc., Novato, CA 94949; and.
6
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.
7
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.

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.

PMID:
25267636
PMCID:
PMC4205671
DOI:
10.1073/pnas.1416660111
[Indexed for MEDLINE]
Free PMC Article

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