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.
| Original language | English |
|---|---|
| Pages (from-to) | 10373-8 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 103 |
| Issue number | 27 |
| DOIs | |
| Publication status | Published - 5 Jul 2006 |
Keywords
- Animals
- Body Weight
- Disease Models, Animal
- Gene Expression Regulation, Enzymologic
- Genetic Therapy
- Genetic Vectors
- Glycosphingolipids
- Inflammation
- Mice
- Mice, Knockout
- Microscopy, Electron
- Protein Subunits
- Survival Rate
- Tay-Sachs Disease
- beta-N-Acetylhexosaminidases
- Journal Article
- Research Support, Non-U.S. Gov't
