CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector

Gene therapy using recombinant adeno-associated viral (AAV) vectors is emerging as a promising approach to treat central nervous system disorders such as Spinal muscular atrophy, Batten, Parkinson and Alzheimer disease amongst others. A critical remaining challenge for central nervous system-targete...

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Main Authors:	Giridhar Murlidharan, Kensuke Sakamoto, Lavanya Rao, Travis Corriher, Dan Wang, Guangping Gao, Patrick Sullivan, Aravind Asokan
Format:	Article
Language:	English
Published:	Elsevier 2016-01-01
Series:	Molecular Therapy: Nucleic Acids
Online Access:	http://www.sciencedirect.com/science/article/pii/S2162253117300628

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spelling	doaj-2c9ca82f1b1840bcafc8ae0e9be055532020-11-25T00:18:39ZengElsevierMolecular Therapy: Nucleic Acids2162-25312016-01-015C10.1038/mtna.2016.49CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV VectorGiridhar Murlidharan0Kensuke Sakamoto1Lavanya Rao2Travis Corriher3Dan Wang4Guangping Gao5Patrick Sullivan6Aravind Asokan7Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USADepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAGene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USAGene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USADepartment of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAGene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAGene therapy using recombinant adeno-associated viral (AAV) vectors is emerging as a promising approach to treat central nervous system disorders such as Spinal muscular atrophy, Batten, Parkinson and Alzheimer disease amongst others. A critical remaining challenge for central nervous system-targeted gene therapy, silencing or gene editing is to limit potential vector dose-related toxicity in off-target cells and organs. Here, we characterize a lab-derived AAV chimeric (AAV2g9), which displays favorable central nervous system attributes derived from both parental counterparts, AAV2 and AAV9. This synthetic AAV strain displays preferential, robust, and widespread neuronal transduction within the brain and decreased glial tropism. Importantly, we observed minimal systemic leakage, decreased sequestration and gene transfer in off-target organs with AAV2g9, when administered into the cerebrospinal fluid. A single intracranial injection of AAV2g9 vectors encoding guide RNAs targeting the schizophrenia risk gene MIR137 (encoding MIR137) in CRISPR/Cas9 knockin mice resulted in brain-specific gene deletion with no detectable events in the liver. This engineered AAV vector is a promising platform for treating neurological disorders through gene therapy, silencing or editing modalities.http://www.sciencedirect.com/science/article/pii/S2162253117300628
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Giridhar Murlidharan Kensuke Sakamoto Lavanya Rao Travis Corriher Dan Wang Guangping Gao Patrick Sullivan Aravind Asokan
spellingShingle	Giridhar Murlidharan Kensuke Sakamoto Lavanya Rao Travis Corriher Dan Wang Guangping Gao Patrick Sullivan Aravind Asokan CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector Molecular Therapy: Nucleic Acids
author_facet	Giridhar Murlidharan Kensuke Sakamoto Lavanya Rao Travis Corriher Dan Wang Guangping Gao Patrick Sullivan Aravind Asokan
author_sort	Giridhar Murlidharan
title	CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector
title_short	CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector
title_full	CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector
title_fullStr	CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector
title_full_unstemmed	CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector
title_sort	cns-restricted transduction and crispr/cas9-mediated gene deletion with an engineered aav vector
publisher	Elsevier
series	Molecular Therapy: Nucleic Acids
issn	2162-2531
publishDate	2016-01-01
description	Gene therapy using recombinant adeno-associated viral (AAV) vectors is emerging as a promising approach to treat central nervous system disorders such as Spinal muscular atrophy, Batten, Parkinson and Alzheimer disease amongst others. A critical remaining challenge for central nervous system-targeted gene therapy, silencing or gene editing is to limit potential vector dose-related toxicity in off-target cells and organs. Here, we characterize a lab-derived AAV chimeric (AAV2g9), which displays favorable central nervous system attributes derived from both parental counterparts, AAV2 and AAV9. This synthetic AAV strain displays preferential, robust, and widespread neuronal transduction within the brain and decreased glial tropism. Importantly, we observed minimal systemic leakage, decreased sequestration and gene transfer in off-target organs with AAV2g9, when administered into the cerebrospinal fluid. A single intracranial injection of AAV2g9 vectors encoding guide RNAs targeting the schizophrenia risk gene MIR137 (encoding MIR137) in CRISPR/Cas9 knockin mice resulted in brain-specific gene deletion with no detectable events in the liver. This engineered AAV vector is a promising platform for treating neurological disorders through gene therapy, silencing or editing modalities.
url	http://www.sciencedirect.com/science/article/pii/S2162253117300628
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CNS-restricted Transduction and CRISPR/Cas9-mediated Gene Deletion with an Engineered AAV Vector

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