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Guanidinylated Neomycin Conjugation Enhances Intranasal Enzyme Replacement in the Brain.

Authors
  • Tong, Wenyong1
  • Dwyer, Chrissa A1
  • Thacker, Bryan E2
  • Glass, Charles A2
  • Brown, Jillian R2
  • Hamill, Kristina3
  • Moremen, Kelley W4
  • Sarrazin, Stéphane1
  • Gordts, Philip L S M5
  • Dozier, Lara E6
  • Patrick, Gentry N6
  • Tor, Yitzhak3
  • Esko, Jeffrey D7
  • 1 Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093-0687, USA.
  • 2 TEGA Therapeutics, Inc., 9500 Gilman Drive, La Jolla, CA 92093-0713, USA.
  • 3 Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093-0358, USA.
  • 4 Department of Biochemistry, Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA. , (Georgia)
  • 5 Department of Medicine, University of California, San Diego, La Jolla, CA 92093-0687, USA.
  • 6 Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093-0366 USA.
  • 7 Department of Cellular and Molecular Medicine, Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA 92093-0687, USA. Electronic address: [email protected]
Type
Published Article
Journal
Molecular Therapy
Publisher
Elsevier
Publication Date
Aug 12, 2017
Identifiers
DOI: 10.1016/j.ymthe.2017.08.007
PMID: 28958576
Source
Medline
Keywords
License
Unknown

Abstract

Iduronidase (IDUA)-deficient mice accumulate glycosaminoglycans in cells and tissues and exhibit many of the same neuropathological symptoms of patients suffering from Mucopolysaccharidosis I. Intravenous enzyme-replacement therapy for Mucopolysaccharidosis I ameliorates glycosaminoglycan storage and many of the somatic aspects of the disease but fails to treat neurological symptoms due to poor transport across the blood-brain barrier. In this study, we examined the delivery of IDUA conjugated to guanidinoneomycin (GNeo), a molecular transporter. GNeo-IDUA and IDUA injected intravenously resulted in reduced hepatic glycosaminoglycan accumulation but had no effect in the brain due to fast clearance from the circulation. In contrast, intranasally administered GNeo-IDUA entered the brain rapidly. Repetitive intranasal treatment with GNeo-IDUA reduced glycosaminoglycan storage, lysosome size and number, and neurodegenerative astrogliosis in the olfactory bulb and primary somatosensory cortex, whereas IDUA was less effective. The enhanced efficacy of GNeo-IDUA was not the result of increased nose-to-brain delivery or enzyme stability, but rather due to more efficient uptake into neurons and astrocytes. GNeo conjugation also enhanced glycosaminoglycan clearance by intranasally delivered sulfamidase to the brain of sulfamidase-deficient mice, a model of Mucopolysaccharidosis IIIA. These findings suggest the general utility of the guanidinoglycoside-based delivery system for restoring missing lysosomal enzymes in the brain.

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