Abstract |
Tay-Sachs disease is a prototypic neurodegenerative disease. Lysosomal storage of GM2 ganglioside in Tay-Sachs and the related disorder, Sandhoff disease, is caused by deficiency of beta-hexosaminidase A, a heterodimeric protein. Tay-Sachs-related diseases ( GM2 gangliosidoses) are incurable, but gene therapy has the potential for widespread correction of the underlying lysosomal defect by means of the secretion-recapture cellular pathway for enzymatic complementation. Sandhoff mice, lacking the beta-subunit of hexosaminidase, manifest many signs of classical human Tay-Sachs disease and, with an acute course, die before 20 weeks of age. We treated Sandhoff mice by stereotaxic intracranial inoculation of recombinant adeno-associated viral vectors encoding the complementing human beta-hexosaminidase alpha and beta subunit genes and elements, including an HIV tat sequence, to enhance protein expression and distribution. Animals survived for >1 year with sustained, widespread, and abundant enzyme delivery in the nervous system. Onset of the disease was delayed with preservation of motor function; inflammation and GM2 ganglioside storage in the brain and spinal cord was reduced. Gene delivery of beta-hexosaminidase A by using adeno-associated viral vectors has realistic potential for treating the human Tay-Sachs-related diseases.
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Authors | M Begoña Cachón-González, Susan Z Wang, Andrew Lynch, Robin Ziegler, Seng H Cheng, Timothy M Cox |
Journal | Proceedings of the National Academy of Sciences of the United States of America
(Proc Natl Acad Sci U S A)
Vol. 103
Issue 27
Pg. 10373-10378
(Jul 05 2006)
ISSN: 0027-8424 [Print] United States |
PMID | 16801539
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Glycosphingolipids
- Protein Subunits
- beta-N-Acetylhexosaminidases
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Topics |
- Animals
- Body Weight
(genetics)
- Disease Models, Animal
- Gene Expression Regulation, Enzymologic
- Genetic Therapy
(methods)
- Genetic Vectors
(genetics)
- Glycosphingolipids
(metabolism)
- Inflammation
(genetics, metabolism, pathology, prevention & control)
- Mice
- Mice, Knockout
- Microscopy, Electron
- Protein Subunits
(genetics, metabolism)
- Survival Rate
- Tay-Sachs Disease
(genetics, metabolism, pathology, therapy)
- beta-N-Acetylhexosaminidases
(deficiency, genetics, metabolism)
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