Date of Award

January 2022

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

David H. Stitelman

Abstract

Detection of monogenic diseases in fetuses can be accomplished prenatally, but therapeutic management of the diseases is most often restricted to supportive treatment for the affected patients postnatally. Prenatal correction of the underlying genetic mechanisms responsible could shift the framework of therapy from supportive treatment of devastating diseases to cure. Gene editing reagents can be delivered to a fetus via systemic delivery of nanoparticles and characteristics of the nanoparticles such as size and composition can be altered to maximize delivery to target organs. This thesis will address systemic delivery of nanoparticles to fetal mice and present work which shows that nanoparticles with varying characteristics can be delivered to fetal mouse pancreas and liver via intravascular injection of fetal mice and can result in up to 1.3% gene editing in the pancreas, as evaluated by droplet digital PCR. Work will also be presented that suggests nanoparticles made with PACE are superior to nanoparticles made with PLGA when the pancreas is targeted. Additionally, immunohistochemical analysis will be used to assess endocrine cell populations within the pancreas and can be used to further elucidate which cell populations nanoparticles could reach in monogenetic diseases of the pancreas, such as cystic fibrosis and hyperinsulinism.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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