Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2727-2742 |
| Number of pages | 16 |
| Journal | Molecular Therapy |
| Volume | 25 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2017 |
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AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy. / Morabito, G; Giannelli, SG; Ordazzo, G; Bido, S; Castoldi, V; Indrigo, M; Cabassi, T; Cattaneo, S.; Luoni, Mirko; Cancellieri, Cinzia; Sessa, A; Bacigaluppi, M; Taverna, S; Leocani, L; Lanciego, JL; Broccoli, V.
In: Molecular Therapy, Vol. 25, No. 12, 2017, p. 2727-2742.Research output: Contribution to journal › Article
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TY - JOUR
T1 - AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy
AU - Morabito, G
AU - Giannelli, SG
AU - Ordazzo, G
AU - Bido, S
AU - Castoldi, V
AU - Indrigo, M
AU - Cabassi, T
AU - Cattaneo, S.
AU - Luoni, Mirko
AU - Cancellieri, Cinzia
AU - Sessa, A
AU - Bacigaluppi, M
AU - Taverna, S
AU - Leocani, L
AU - Lanciego, JL
AU - Broccoli, V
PY - 2017
Y1 - 2017
N2 - The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of α-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV-PHP.B-GBA1 restored physiological levels of the enzyme, reduced α-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies. Extensive gene delivery in the CNS is attainable through a single systemic injection of AAV-PHP.B. The authors exploited this system to simultaneously target different brain areas and modulate their functions but also to unveil its therapeutic potential. Global transduction of a therapeutic gene reversed pathological symptoms in a model of synucleinopathy. © 2017 The American Society of Gene and Cell Therapy.
AB - The lack of technology for direct global-scale targeting of the adult mouse nervous system has hindered research on brain processing and dysfunctions. Currently, gene transfer is normally achieved by intraparenchymal viral injections, but these injections target a restricted brain area. Herein, we demonstrated that intravenous delivery of adeno-associated virus (AAV)-PHP.B viral particles permeated and diffused throughout the neural parenchyma, targeting both the central and the peripheral nervous system in a global pattern. We then established multiple procedures of viral transduction to control gene expression or inactivate gene function exclusively in the adult nervous system and assessed the underlying behavioral effects. Building on these results, we established an effective gene therapy strategy to counteract the widespread accumulation of α-synuclein deposits throughout the forebrain in a mouse model of synucleinopathy. Transduction of A53T-SCNA transgenic mice with AAV-PHP.B-GBA1 restored physiological levels of the enzyme, reduced α-synuclein pathology, and produced significant behavioral recovery. Finally, we provided evidence that AAV-PHP.B brain penetration does not lead to evident dysfunctions in blood-brain barrier integrity or permeability. Altogether, the AAV-PHP.B viral platform enables non-invasive, widespread, and long-lasting global neural expression of therapeutic genes, such as GBA1, providing an invaluable approach to treat neurodegenerative diseases with diffuse brain pathology such as synucleinopathies. Extensive gene delivery in the CNS is attainable through a single systemic injection of AAV-PHP.B. The authors exploited this system to simultaneously target different brain areas and modulate their functions but also to unveil its therapeutic potential. Global transduction of a therapeutic gene reversed pathological symptoms in a model of synucleinopathy. © 2017 The American Society of Gene and Cell Therapy.
U2 - 10.1016/j.ymthe.2017.08.004
DO - 10.1016/j.ymthe.2017.08.004
M3 - Article
VL - 25
SP - 2727
EP - 2742
JO - Molecular Therapy
JF - Molecular Therapy
SN - 1525-0016
IS - 12
ER -