Date of Award

8-2025

Document Type

Thesis

Degree Name

Master of Science (MS)

College/School

College of Science and Mathematics

Department/Program

Biology

Thesis Sponsor/Dissertation Chair/Project Chair

Christos Suriano

Committee Member

James Campanella

Committee Member

Carlos Molina

Abstract

Virally-mediated gene delivery has emerged as a promising approach for treating monogenic disorders in FDA-approved human gene therapies as well as advancing basic neuroscience research. However, immune recognition of these viral vectors, especially through the innate immune detector Toll-like receptor 9 (TLR9), can trigger neuroinflammation and off-target neuroimmune effects. Toll-like receptor 9 -mediated immune responses include the upregulation of major histocompatibility complex I (MHCI) and complement component C3, which are known to influence synaptic pruning and neuronal complexity. Past studies have described subtoxic effects of AAV in the cortex of 8-10 week old male mice, however, baseline sex- and age-based differences in neuro-immune function may alter the brain’s response to AAV-mediated gene delivery. Our research includes neuro-immune expression in female and older mice to determine if there are potential sex-or age-based differences in the immunogenicity of AAV. Our pilot study identifies sex- and age-dependent differential expression patterns of TLR9, MHCI H2-K and H2-D, PSD95, and C3 across different tissues— prefrontal cortex, spleen, and spinal cord in juvenile and geriatric mice. These results highlight the necessity for personalized approaches that consider biological sex and age in the development and application of viral-vector-based therapeutics.

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