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dc.contributor.advisorGuangping Gaoen_US
dc.contributor.advisorRobert H. Brown Jr.en_US
dc.contributor.authorYang, Huiya
dc.date.accessioned2022-09-20T16:47:18Z
dc.date.available2022-09-20T16:47:18Z
dc.date.issued2022-08-22
dc.identifier.doi10.13028/tw1m-p660en_US
dc.identifier.urihttp://hdl.handle.net/20.500.14038/51130
dc.description.abstractGlycosphingolipids (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.en_US
dc.language.isoen_USen_US
dc.publisherUMass Chan Medical Schoolen_US
dc.rightsCopyright © 2022 Yang.en_US
dc.rights.uriAll Rights Reserveden_US
dc.subjectGlycosphingolipidsen_US
dc.subjectGM3 synthase deficiency (GM3SD)en_US
dc.subjecthereditary sensory and autonomic neuropathy type 1A (HSAN1A)en_US
dc.subjectgene replacement therapyen_US
dc.titleRegulated Gene Therapy Towards Glycosphingolipid Biosynthesis Deficienciesen_US
dc.typeDoctoral Dissertationen_US
dc.contributor.departmentHorae Gene Therapy Centeren_US
dc.contributor.departmentNeurologyen_US
dc.description.thesisprogramInterdisciplinaryen_US
dc.identifier.orcid0000-0001-5783-125Xen_US


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