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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Authors | Xiufang Pan, Scott A Sands, Yongping Yue, Keqing Zhang, Steven M LeVine, Dongsheng Duan |
Journal | Human gene therapy
(Hum Gene Ther)
Vol. 30
Issue 9
Pg. 1039-1051
(09 2019)
ISSN: 1557-7422 [Electronic] United States |
PMID | 31184217
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Animals
- Dependovirus
(genetics)
- Disease Models, Animal
- Enzyme Activation
- Galactosylceramidase
(genetics, metabolism)
- Gene Expression
- Gene Order
- Gene Transfer Techniques
- Genetic Engineering
- Genetic Therapy
(methods)
- Genetic Vectors
(administration & dosage, genetics, isolation & purification)
- Leukodystrophy, Globoid Cell
(genetics, metabolism, physiopathology, therapy)
- Mice
- Phenotype
- Transduction, Genetic
- Transgenes
- Treatment Outcome
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