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    A Multifaceted Approach to Optimizing AAV Delivery to the Brain for the Treatment of Neurodegenerative Diseases

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    Author
    Fischell, Jonathan M
    Fishman, Paul S
    Date
    2021-09-24
    Journal
    Frontiers in Neuroscience
    Publisher
    Frontiers Media S.A.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.frontiersin.org/articles/10.3389/fnins.2021.747726/full
    Abstract
    Despite major advancements in gene therapy technologies, there are no approved gene therapies for diseases which predominantly effect the brain. Adeno-associated virus (AAV) vectors have emerged as the most effective delivery vector for gene therapy owing to their simplicity, wide spread transduction and low immunogenicity. Unfortunately, the blood-brain barrier (BBB) makes IV delivery of AAVs, to the brain highly inefficient. At IV doses capable of widespread expression in the brain, there is a significant risk of severe immune-mediated toxicity. Direct intracerebral injection of vectors is being attempted. However, this method is invasive, and only provides localized delivery for diseases known to afflict the brain globally. More advanced methods for AAV delivery will likely be required for safe and effective gene therapy to the brain. Each step in AAV delivery, including delivery route, BBB transduction, cellular tropism and transgene expression provide opportunities for innovative solutions to optimize delivery efficiency. Intra-arterial delivery with mannitol, focused ultrasound, optimized AAV capsid evolution with machine learning algorithms, synthetic promotors are all examples of advanced strategies which have been developed in pre-clinical models, yet none are being investigated in clinical trials. This manuscript seeks to review these technological advancements, and others, to improve AAV delivery to the brain, and to propose novel strategies to build upon this research. Ultimately, it is hoped that the optimization of AAV delivery will allow for the human translation of many gene therapies for neurodegenerative and other neurologic diseases.
    Rights/Terms
    Copyright © 2021 Fischell and Fishman.
    Keyword
    adeno-associated virus (AAV)
    blood–brain barrier disruption
    capsid engineering
    gene therapy
    genetic vectors
    intra-arterial (IA) delivery
    intra-thecal drug delivery systems
    neurodegenerative disease
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/16854
    ae974a485f413a2113503eed53cd6c53
    10.3389/fnins.2021.747726
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