Dissertation/Thesis Abstract

Development of a Stem Cell Gene Therapy for Sanfilippo Syndrome Type B
by Clarke, Don Lucas, M.S., California State University, Los Angeles, 2017, 36; 10278830
Abstract (Summary)

Sanfilippo syndrome type B (Mucopolysaccharidosis type IIIB; MPS IIIB) is a lysosomal storage disorder affecting primarily the brain and is characterized by profound intellectual disability, dementia, and a lifespan of about twenty years. The cause is a mutation in the gene encoding α– N-acetylglucosaminidase (NAGLU), a lysosomal enzyme, leading to the deficiency of NAGLU and accumulation of heparan sulfate. I am investigating a stem cell gene therapy approach in a Naglu-/- mouse model. I think that iNSCs overexpressing NAGLU can engraft and reduce neural pathology in the mouse model. Here I report that NAGLU overexpressed in neural stem cells derived from induced pluripotent stem cells (iNSCs) is capable of being taken up by deficient cells. I used flow cytometry and Lysotracker to demonstrate that NAGLU can reduce deficient cells’ lysosomal volume in vitro, suggesting that NAGLU treatment has a biological effect. iNSCs overexpressing NAGLU were injected into the brains of 1 day old Naglu-/- mice. iNSCs were detected 10 weeks after injection. Brain sections possessed NAGLU activity greater than or equal to heterozygous controls, activity was detected distal to injection sites, and transplanted animals showed reduction in LAMP1, GFAP, and CD68. The results suggest that engineered iNSCs could be used to deliver enzyme and treat MPS IIIB.

Indexing (document details)
Advisor: Iacovino, Michelina
Commitee: Eivers, Edward, Nissen, Robert, Porter, Edith
School: California State University, Los Angeles
Department: Biological Sciences
School Location: United States -- California
Source: MAI 56/04M(E), Masters Abstracts International
Subjects: Biology, Molecular biology
Keywords: Gene therapy, Lysosomal storage disorder, MPSIIIB, NAGLU, Rare disease, Sanfilippo
Publication Number: 10278830
ISBN: 9781369847758
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