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An Engineered Galactosylceramidase Construct Improves AAV Gene Therapy for Krabbe Disease in Twitcher Mice.

Authors
  • Pan, Xiufang1
  • Sands, Scott A2
  • Yue, Yongping1
  • Zhang, Keqing1
  • LeVine, Steven M2
  • Duan, Dongsheng1, 3, 4, 5
  • 1 Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, Missouri.
  • 2 Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas.
  • 3 Department of Neurology, School of Medicine, University of Missouri, Columbia, Missouri.
  • 4 Department of Veterinary Biomedical Sciences, College of Veterinary Medicine, University of Missouri, Columbia, Missouri.
  • 5 Department of Biomedical, Biological & Chemical Engineering, College of Engineering, University of Missouri, Columbia, Missouri.
Type
Published Article
Journal
Human Gene Therapy
Publisher
Mary Ann Liebert
Publication Date
Sep 01, 2019
Volume
30
Issue
9
Pages
1039–1051
Identifiers
DOI: 10.1089/hum.2019.008
PMID: 31184217
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Krabbe disease is an inherited neurodegenerative disease caused by mutations in the galactosylceramidase gene. In the infantile form, patients die before 3 years of age. Systemic adeno-associated virus serotype 9 (AAV9) gene therapy was recently shown to reverse the disease course in human patients in another lethal infantile neurodegenerative disease. To explore AAV9 therapy for Krabbe disease, we engineered a codon-optimized AAV9 galactosylceramidase vector. We further incorporated features to allow AAV9-derived galactosylceramidase to more efficiently cross the blood-brain barrier and be secreted from transduced cells. We tested the optimized vector by a single systemic injection in the twitcher mouse, an authentic Krabbe disease model. Untreated twitcher mice showed characteristic neuropathology and motion defects. They died prematurely with a median life span of 41 days. Intravenous injection in 2-day-old twitcher mice reduced central and peripheral neuropathology and significantly improved the gait pattern and body weight. Noticeably, the median life span was extended to 150 days. Intraperitoneal injection in 6- to 12-day-old twitcher mice also significantly improved the motor function, body weight, and median life span (to 104 days). Our results far exceed the ≤70 days median life span seen in all reported stand-alone systemic AAV therapies. Our study highlights the importance of vector engineering for Krabbe disease gene therapy. The engineered vector warrants further development.

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