Preclinical differences of intravascular aav9 delivery to neurons and glia: A comparative study of adult mice and nonhuman primates

Steven J. Gray, Valerie Matagne, Lavanya Bachaboina, Swati Yadav, Sergio Ojeda, R. Jude Samulski

    Research output: Contribution to journalArticle

    235 Citations (Scopus)

    Abstract

    Other labs have previously reported the ability of adeno-associated virus serotype 9 (AAV9) to cross the blood-brain barrier (BBB). In this report, we carefully characterized variables that might affect AAV9's efficiency for central nervous system (CNS) transduction in adult mice, including dose, vehicle composition, mannitol coadministration, and use of single-stranded versus self-complementary AAV. We report that AAV9 is able to transduce approximately twice as many neurons as astrocytes across the entire extent of the adult rodent CNS at doses of 1.25 × 1012, 1 × 1013, and 8 × 1013 vg/kg. Vehicle composition or mannitol coadministration had only modest effects on CNS transduction, suggesting AAV9 crosses the BBB by an active transport mechanism. Self-complementary vectors were greater than tenfold more efficient than single-stranded vectors. When this approach was applied to juvenile nonhuman primates (NHPs) at the middle dose (9-9.5 × 1012 vg/kg) tested in mice, a reduction in peripheral organ and brain transduction was observed compared to mice, along with a clear shift toward mostly glial transduction. Moreover, the presence of low levels of pre-existing neutralizing antibodies (NAbs) mostly occluded CNS and peripheral transduction using this delivery approach. Our results indicate that high peripheral tropism, limited neuronal transduction in NHPs, and pre-existing NAbs represent significant barriers to human translation of intravascular AAV9 delivery.

    Original languageEnglish (US)
    Pages (from-to)1058-1069
    Number of pages12
    JournalMolecular Therapy
    Volume19
    Issue number6
    DOIs
    StatePublished - Jun 2011

    Fingerprint

    Dependovirus
    Neuroglia
    Primates
    Central Nervous System
    Neurons
    Mannitol
    Neutralizing Antibodies
    Blood-Brain Barrier
    Tropism
    Active Biological Transport
    Astrocytes
    Rodentia
    Serogroup
    Brain

    ASJC Scopus subject areas

    • Molecular Biology
    • Molecular Medicine
    • Genetics
    • Drug Discovery
    • Pharmacology

    Cite this

    Preclinical differences of intravascular aav9 delivery to neurons and glia : A comparative study of adult mice and nonhuman primates. / Gray, Steven J.; Matagne, Valerie; Bachaboina, Lavanya; Yadav, Swati; Ojeda, Sergio; Samulski, R. Jude.

    In: Molecular Therapy, Vol. 19, No. 6, 06.2011, p. 1058-1069.

    Research output: Contribution to journalArticle

    Gray, Steven J. ; Matagne, Valerie ; Bachaboina, Lavanya ; Yadav, Swati ; Ojeda, Sergio ; Samulski, R. Jude. / Preclinical differences of intravascular aav9 delivery to neurons and glia : A comparative study of adult mice and nonhuman primates. In: Molecular Therapy. 2011 ; Vol. 19, No. 6. pp. 1058-1069.
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