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    Regulated Gene Therapy Towards Glycosphingolipid Biosynthesis Deficiencies

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    Name:
    Yang_Huiya_Dissertation_0822_2 ...
    Embargo:
    2024-08-26
    Size:
    197.4Mb
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    Authors
    Yang, Huiya
    Faculty Advisor
    Guangping Gao; Robert H. Brown Jr.
    Academic Program
    Interdisciplinary
    UMass Chan Affiliations
    Horae Gene Therapy Center
    Neurology
    Document Type
    Doctoral Dissertation
    Publication Date
    2022-08-22
    Keywords
    Glycosphingolipids
    GM3 synthase deficiency (GM3SD)
    hereditary sensory and autonomic neuropathy type 1A (HSAN1A)
    gene replacement therapy
    
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    Abstract
    Glycosphingolipids (GSLs) are a group of amphipathic glycolipids essential for maintaining the normal ultrastructure and function of neural and oligodendrocyte cell membranes throughout the mammalian central nervous system (CNS). De novo GSL biosynthesis defects cause severe neurological diseases such as GM3 synthase deficiency (GM3SD) and hereditary sensory and autonomic neuropathy type 1A (HSAN1A), each lacking effective treatment. Here, we developed two distinct potential therapeutic approaches for these neurological diseases. For GM3SD that is caused by loss-of-function mutations in ST3GAL5, we employed a recombinant adeno-associated virus (rAAV)-mediated human ST3GAL5 gene replacement therapy. First, using ST3GAL5 mutant patient iPSC-derived neurons and St3gal5 knock-out mouse models, we have achieved ST3GAL5 gene normalization and restoration of the functional products, cerebral gangliosides. Importantly, we revealed the hepatic toxicity caused by ubiquitous expression of ST3GAL5 and optimized a CNS-restricted rAAV gene replacement therapy for the safe and efficacious rescue of the severe neurodevelopmental phenotypes and early lethality in disease mouse models, given by both intracerebroventricular and intravenous routes of administration. These results support for further clinical development of ST3GAL5 gene therapy. On the other hand, to target gain-of-function SPTLC1 mutation caused HSAN1A, we screened antisense oligonucleotides (ASOs) and achieved efficient reduction of mutant SPTLC1 transcripts and its toxic products in patient-fibroblasts. In summary, this thesis describes the potential of novel rAAV-mediated gene replacement therapy in GM3SD and allele-specific ASO silencing in HSAN1A, highlighting the significance of personalized gene therapy for monogenic neurological disorders.
    DOI
    10.13028/tw1m-p660
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/51130
    Rights
    Copyright © 2022 Yang.
    Distribution License
    All Rights Reserved
    ae974a485f413a2113503eed53cd6c53
    10.13028/tw1m-p660
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    Morningside Graduate School of Biomedical Sciences Dissertations and Theses

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