• Login
    View Item 
    •   Home
    • UMass Chan Student Research and Publications
    • Morningside Graduate School of Biomedical Sciences
    • Morningside Graduate School of Biomedical Sciences Dissertations and Theses
    • View Item
    •   Home
    • UMass Chan Student Research and Publications
    • Morningside Graduate School of Biomedical Sciences
    • Morningside Graduate School of Biomedical Sciences Dissertations and Theses
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of eScholarship@UMassChanCommunitiesPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywordsThis CollectionPublication DateAuthorsUMass Chan AffiliationsTitlesDocument TypesKeywords

    My Account

    LoginRegister

    Help

    AboutSubmission GuidelinesData Deposit PolicySearchingAccessibilityTerms of UseWebsite Migration FAQ

    Statistics

    Most Popular ItemsStatistics by CountryMost Popular Authors

    Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses

    • CSV
    • RefMan
    • EndNote
    • BibTex
    • RefWorks
    Thumbnail
    Name:
    Golebiowski_Diane_reduced_size.pdf
    Size:
    2.629Mb
    Format:
    PDF
    Download
    Authors
    Golebiowski, Diane L.
    Faculty Advisor
    Miguel Sena-Esteves, PhD
    Academic Program
    Interdisciplinary Graduate Program
    UMass Chan Affiliations
    Neurology, Gene Therapy Center
    Document Type
    Doctoral Dissertation
    Publication Date
    2016-09-01
    Keywords
    AAV
    Gene therapy
    CNS
    Tay-sachs disease
    Sandhoff disease
    GM2 gangliosidosis
    Disease Modeling
    Enzymes and Coenzymes
    Molecular Biology
    Nervous System Diseases
    Other Neuroscience and Neurobiology
    Pharmacology
    Toxicology
    Translational Medical Research
    Show allShow less
    
    Metadata
    Show full item record
    Abstract
    GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose.
    DOI
    10.13028/M22C8K
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/32273
    Rights
    Copyright is held by the author, with all rights reserved.
    ae974a485f413a2113503eed53cd6c53
    10.13028/M22C8K
    Scopus Count
    Collections
    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

    entitlement

     
    DSpace software (copyright © 2002 - 2023)  DuraSpace
    Lamar Soutter Library, UMass Chan Medical School | 55 Lake Avenue North | Worcester, MA 01655 USA
    Quick Guide | escholarship@umassmed.edu
    Open Repository is a service operated by 
    Atmire NV
     

    Export search results

    The export option will allow you to export the current search results of the entered query to a file. Different formats are available for download. To export the items, click on the button corresponding with the preferred download format.

    By default, clicking on the export buttons will result in a download of the allowed maximum amount of items.

    To select a subset of the search results, click "Selective Export" button and make a selection of the items you want to export. The amount of items that can be exported at once is similarly restricted as the full export.

    After making a selection, click one of the export format buttons. The amount of items that will be exported is indicated in the bubble next to export format.