Abstract | OBJECTIVE: METHODS: At birth, Ppt1(-/-) and wild-type mice were given either intracranial injections of AAV2/5-PPT1 or bone marrow transplantation, separately as well as in combination. To assess function, we measured rotorod performance monthly as well as lifespan. At terminal time points, we evaluated the therapeutic effects on several INCL-specific parameters, such as cortical thickness, autofluorescent accumulation, and glial activation. Finally, we determined levels of PPT1 enzyme activity and bone marrow engraftment in treated mice. RESULTS: AAV2/5-mediated gene therapy alone resulted in significant histological correction, improved motor function, and increased lifespan. Interestingly, the addition of BMT further increased the lifespan of treated mice and led to dramatic, sustained improvements in motor function. These data are truly striking, given that BMT alone is ineffective, yet it synergizes with CNS-directed gene therapy to dramatically increase efficacy and lifespan. INTERPRETATION: AAV2/5-mediated gene therapy in combination with BMT provides an unprecedented increase in lifespan as well as dramatic improvement on functional and histological parameters.
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Authors | Shannon L Macauley, Marie S Roberts, Andrew M Wong, Francesca McSloy, Adarsh S Reddy, Jonathan D Cooper, Mark S Sands |
Journal | Annals of neurology
(Ann Neurol)
Vol. 71
Issue 6
Pg. 797-804
(Jun 2012)
ISSN: 1531-8249 [Electronic] United States |
PMID | 22368049
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 American Neurological Association. |
Chemical References |
- Thiolester Hydrolases
- palmitoyl-protein thioesterase
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Topics |
- Age Factors
- Animals
- Animals, Newborn
- Bone Marrow Transplantation
(methods)
- Brain
(metabolism, pathology)
- Dependovirus
(genetics)
- Disease Models, Animal
- Female
- Genetic Therapy
(methods)
- Genetic Vectors
(administration & dosage)
- Male
- Mice
- Mice, Knockout
- Motor Activity
- Neuronal Ceroid-Lipofuscinoses
(pathology, physiopathology, therapy)
- Rotarod Performance Test
- Thiolester Hydrolases
(biosynthesis, deficiency, therapeutic use)
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