Graduation Year
2024
Document Type
Master's Thesis
Degree
Master of Science
Program
Biological Science
Program Director
Meredith Protas, PhD
First Reader
Jennifer Leedy
Second Reader
Manuel Lopez
Abstract
Many genetic epilepsies and neurodevelopmental disorders such as Dravet Syndrome are caused by haploinsufficiency of genes involved in synaptic transmission. Oligonucleotides show promise to target these genes and upregulate protein expression; however, these therapeutics can be difficult to translate preclinically as many synaptic genes show low sequence homology between rodents and humans. Thus, we generated an in-house human neuronal xenograft (HuNeuX) mouse model by transplanting human neurons into the mouse host via intraparenchymal brain injection. We evaluated different factors that would make the host environment permissive for transplant survival, including the degree of host immune deficiency required and optimal host age. Finally, to demonstrate the functionality of the model, we dosed HuNeuX mice with an antisense oligonucleotide (ASO) known to increase SCN1A expression, the gene that is haploinsufficient in Dravet syndrome. If ASO20N increased gene expression in transplanted human neuron population within the murine brain, this would confirm the utility of the model. This work proposes the HuNeuX model as a useful tool to assess human-neuronal specific genetic target engagement in vivo across central nervous system (CNS) indications.