Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65

Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross the blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities for non-invasive brain delivery. Anc80L65, a novel...

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Main Authors:	Eloise Hudry, Eva Andres-Mateos, Eli P. Lerner, Adrienn Volak, Olivia Cohen, Bradley T. Hyman, Casey A. Maguire, Luk H. Vandenberghe
Format:	Article
Language:	English
Published:	Elsevier 2018-09-01
Series:	Molecular Therapy: Methods & Clinical Development
Online Access:	http://www.sciencedirect.com/science/article/pii/S232905011830069X

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spelling	doaj-7a18b8c93c6f48f5bb927acaec2fa9aa2020-11-25T00:26:42ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012018-09-0110197209Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65Eloise Hudry0Eva Andres-Mateos1Eli P. Lerner2Adrienn Volak3Olivia Cohen4Bradley T. Hyman5Casey A. Maguire6Luk H. Vandenberghe7MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USAMassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USADepartment of Neurology, The Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02114, USAMassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USAMassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USADepartment of Neurology, The Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02114, USAGrousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA; Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA; The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Corresponding author: Luk H. Vandenberghe, PhD, Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary, 20 Staniford Street, Boston, MA 02114, USA.Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross the blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities for non-invasive brain delivery. Anc80L65, a novel AAV capsid designed from in silico reconstruction of the viral evolutionary lineage, has previously demonstrated robust transduction capabilities after local delivery in various tissues such as liver, retina, or cochlea, compared with conventional AAVs. Here, we compared the transduction efficacy of Anc80L65 with conventional AAV9 in the CNS after intravenous, intracerebroventricular (i.c.v.), or intraparenchymal injections. Anc80L65 was more potent at targeting the brain and spinal cord after intravenous injection than AAV9, and mostly transduced astrocytes and a wide range of neuronal subpopulations. Although the efficacy of Anc80L65 and AAV9 is similar after direct intraparenchymal injection in the striatum, Anc80L65’s diffusion throughout the CNS was more extensive than AAV9 after i.c.v. infusion, leading to widespread EGFP expression in the cerebellum. These findings demonstrate that Anc80L65 is a highly efficient gene transfer vector for the murine CNS. Systemic injection of Anc80L65 leads to notable expression in the CNS that does not rely on a self-complementary genome. These data warrant further testing in larger animal models. Keywords: adeno-associated, Anc80L65, AAV, central nervous systemhttp://www.sciencedirect.com/science/article/pii/S232905011830069X
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Eloise Hudry Eva Andres-Mateos Eli P. Lerner Adrienn Volak Olivia Cohen Bradley T. Hyman Casey A. Maguire Luk H. Vandenberghe
spellingShingle	Eloise Hudry Eva Andres-Mateos Eli P. Lerner Adrienn Volak Olivia Cohen Bradley T. Hyman Casey A. Maguire Luk H. Vandenberghe Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65 Molecular Therapy: Methods & Clinical Development
author_facet	Eloise Hudry Eva Andres-Mateos Eli P. Lerner Adrienn Volak Olivia Cohen Bradley T. Hyman Casey A. Maguire Luk H. Vandenberghe
author_sort	Eloise Hudry
title	Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65
title_short	Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65
title_full	Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65
title_fullStr	Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65
title_full_unstemmed	Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65
title_sort	efficient gene transfer to the central nervous system by single-stranded anc80l65
publisher	Elsevier
series	Molecular Therapy: Methods & Clinical Development
issn	2329-0501
publishDate	2018-09-01
description	Adeno-associated viral vectors (AAVs) have demonstrated potential in applications for neurologic disorders, and the discovery that some AAVs can cross the blood-brain barrier (BBB) after intravenous injection has further expanded these opportunities for non-invasive brain delivery. Anc80L65, a novel AAV capsid designed from in silico reconstruction of the viral evolutionary lineage, has previously demonstrated robust transduction capabilities after local delivery in various tissues such as liver, retina, or cochlea, compared with conventional AAVs. Here, we compared the transduction efficacy of Anc80L65 with conventional AAV9 in the CNS after intravenous, intracerebroventricular (i.c.v.), or intraparenchymal injections. Anc80L65 was more potent at targeting the brain and spinal cord after intravenous injection than AAV9, and mostly transduced astrocytes and a wide range of neuronal subpopulations. Although the efficacy of Anc80L65 and AAV9 is similar after direct intraparenchymal injection in the striatum, Anc80L65’s diffusion throughout the CNS was more extensive than AAV9 after i.c.v. infusion, leading to widespread EGFP expression in the cerebellum. These findings demonstrate that Anc80L65 is a highly efficient gene transfer vector for the murine CNS. Systemic injection of Anc80L65 leads to notable expression in the CNS that does not rely on a self-complementary genome. These data warrant further testing in larger animal models. Keywords: adeno-associated, Anc80L65, AAV, central nervous system
url	http://www.sciencedirect.com/science/article/pii/S232905011830069X
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Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65

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