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    Ly6a Differential Expression in Blood-Brain Barrier Is Responsible for Strain Specific Central Nervous System Transduction Profile of AAV-PHP.B

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    Authors
    Batista, Ana Rita
    King, Oliver D.
    Reardon, Christopher P.
    Davis, Crystal
    Shankaracharya, FNU
    Philip, Vivek
    Gray-Edwards, Heather
    Aronin, Neil
    Lutz, Cathleen
    Landers, John E.
    Sena-Esteves, Miguel
    Show allShow less
    UMass Chan Affiliations
    RNA Therapeutics Institute
    Department of Radiology
    Horae Gene Therapy Center
    Department of Neurology
    Document Type
    Journal Article
    Publication Date
    2020-01-01
    Keywords
    Animals
    Antigens, Ly
    Blood-Brain Barrier
    Central Nervous System
    Dependovirus
    Endothelium, Vascular
    Female
    Gene Expression
    Gene Transfer Techniques
    Genes, Reporter
    Genetic Vectors
    Genotype
    Male
    Membrane Proteins
    Mice
    Mice, Transgenic
    Quantitative Trait Loci
    Species Specificity
    Transduction, Genetic
    AAV-PHP.B
    CNS transduction
    Ly6a
    blood–brain barrier
    mouse genetics
    Genetics and Genomics
    Nervous System
    Nervous System Diseases
    Neuroscience and Neurobiology
    Show allShow less
    
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    Link to Full Text
    https://doi.org/10.1089/hum.2019.186
    Abstract
    Adeno-associated virus (AAV) gene therapy for neurological diseases was revolutionized by the discovery that AAV9 crosses the blood-brain barrier (BBB) after systemic administration. Transformative results have been documented in various inherited diseases, but overall neuronal transduction efficiency is relatively low. The recent development of AAV-PHP.B with ∼60-fold higher efficiency than AAV9 in transducing the adult mouse brain was the major first step toward acquiring the ability to deliver genes to the majority of cells in the central nervous system (CNS). However, little is known about the mechanism utilized by AAV to cross the BBB, and how it may diverge across species. In this study, we show that AAV-PHP.B is ineffective for systemic CNS gene transfer in the inbred strains BALB/cJ, BALB/cByJ, A/J, NOD/ShiLtJ, NZO/HILtJ, C3H/HeJ, and CBA/J mice, but it is highly potent in C57BL/6J, FVB/NJ, DBA/2J, 129S1/SvImJ, and AKR/J mice and also the outbred strain CD-1. We used the power of classical genetics to uncover the molecular mechanisms AAV-PHP.B engages to transduce CNS at high efficiency, and by quantitative trait locus mapping we identify a 6 Mb region in chromosome 15 with an logarithm of the odds (LOD) score ∼20, including single nucleotide polymorphisms in the coding region of 9 different genes. Comparison of the publicly available data on the genome sequence of 16 different mouse strains, combined with RNA-seq data analysis of brain microcapillary endothelia, led us to conclude that the expression level of Ly6a is likely the determining factor for differential efficacy of AAV-PHP.B in transducing the CNS across different mouse strains.
    Source

    Batista AR, King OD, Reardon CP, Davis C, Shankaracharya, Philip V, Gray-Edwards H, Aronin N, Lutz C, Landers J, Sena-Esteves M. Ly6a Differential Expression in Blood-Brain Barrier Is Responsible for Strain Specific Central Nervous System Transduction Profile of AAV-PHP.B. Hum Gene Ther. 2020 Jan;31(1-2):90-102. doi: 10.1089/hum.2019.186. Epub 2019 Dec 13. PMID: 31696742.

    DOI
    10.1089/hum.2019.186
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/29846
    PubMed ID
    31696742
    Related Resources

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    ae974a485f413a2113503eed53cd6c53
    10.1089/hum.2019.186
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