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: Shih-Hsin Kan, Mika Aoyagi-Scharber, Steven Q Le, Jon Vincelette, Kazuhiro Ohmi, Sherry Bullens, Daniel J Wendt, Terri M Christianson, Pascale M N Tiger, Jillian R Brown, Roger Lawrence, Bryan K Yip, John Holtzinger, Anil Bagri, Danielle Crippen-Harmon, Kristen N Vondrak, Zhi Chen, Chuck M Hague, Josh C Woloszynek, Diana S Cheung, Katherine A Webster, Evan G Adintori, Melanie J Lo, Wesley Wong, Paul A Fitzpatrick, Jonathan H LeBowitz, Brett E Crawford, Stuart Bunting, Patricia I Dickson, Elizabeth F Neufeld
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 41 Pg. 14870-5 (Oct 14 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25267636 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Lamp1 protein, mouse
• Lysosome-Associated Membrane Glycoproteins
• Recombinant Fusion Proteins
• Insulin-Like Growth Factor II
• Heparitin Sulfate
• alpha-N-acetyl-D-glucosaminidase
• Acetylglucosaminidase
• beta-N-Acetylhexosaminidases

Topics

• Acetylglucosaminidase (therapeutic use)
• Animals
• Biomarkers (metabolism)
• Brain (metabolism, pathology)
• CHO Cells
• Cells, Cultured
• Cricetinae
• Cricetulus
• Drug Delivery Systems
• Endocytosis
• Fibroblasts (metabolism, pathology)
• Heparitin Sulfate (metabolism)
• Humans
• Injections, Intraventricular
• Insulin-Like Growth Factor II (therapeutic use)
• Liver (metabolism)
• Lysosome-Associated Membrane Glycoproteins (metabolism)
• Mice
• Mucopolysaccharidosis III (drug therapy, pathology)
• Neurons (metabolism, pathology)
• Protein Binding
• Recombinant Fusion Proteins (administration & dosage, therapeutic use)
• beta-N-Acetylhexosaminidases (metabolism)