AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy

G Morabito, SG Giannelli, G Ordazzo, S Bido, V Castoldi, M Indrigo, T Cabassi, S. Cattaneo, Mirko Luoni, Cinzia Cancellieri, A Sessa, M Bacigaluppi, S Taverna, L Leocani, JL Lanciego, V Broccoli

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)2727-2742
Number of pages16
JournalMolecular Therapy
Volume25
Issue number12
DOIs
Publication statusPublished - 2017

Fingerprint

Dependovirus
Genetic Therapy
Nervous System
Synucleins
Brain
Genes
Injections
Pathology
Gene Expression
Peripheral Nervous System
Cell- and Tissue-Based Therapy
Prosencephalon
Blood-Brain Barrier
Neurodegenerative Diseases
Virion
Transgenic Mice
Permeability
Therapeutics
Central Nervous System
Technology

Cite this

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 journalArticle

Morabito, G, Giannelli, SG, Ordazzo, G, Bido, S, Castoldi, V, Indrigo, M, Cabassi, T, Cattaneo, S, Luoni, M, Cancellieri, C, Sessa, A, Bacigaluppi, M, Taverna, S, Leocani, L, Lanciego, JL & Broccoli, V 2017, 'AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy', Molecular Therapy, vol. 25, no. 12, pp. 2727-2742. https://doi.org/10.1016/j.ymthe.2017.08.004
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. / AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy. In: Molecular Therapy. 2017 ; Vol. 25, No. 12. pp. 2727-2742.
@article{f2c3b12a96ca42408fea0b0bf11eee0f,
title = "AAV-PHP.B-Mediated Global-Scale Expression in the Mouse Nervous System Enables GBA1 Gene Therapy for Wide Protection from Synucleinopathy",
abstract = "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. {\circledC} 2017 The American Society of Gene and Cell Therapy.",
author = "G Morabito and SG Giannelli and G Ordazzo and S Bido and V Castoldi and M Indrigo and T Cabassi and S. Cattaneo and Mirko Luoni and Cinzia Cancellieri and A Sessa and M Bacigaluppi and S Taverna and L Leocani and JL Lanciego and V Broccoli",
year = "2017",
doi = "10.1016/j.ymthe.2017.08.004",
language = "English",
volume = "25",
pages = "2727--2742",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "12",

}

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 -