Ryan Zenhausern
BME PhD Proposal Presentation
Date: 2024-08-20
Time: 1:30pm - 3:30
Location / Meeting Link: Emory HSRB2 N600; https://emory.zoom.us/j/93405601172
Committee Members:
Dr. James Dahlman, PhD (Advisor); Dr. Karmella A. Haynes, PhD; Dr. Hanjoong Jo, PhD; Dr. Ahmet Coskun, PhD; Dr. Vivien Sheehan, MD, PhD
Title: Development of lipid nanoparticles for RNA delivery to Hematopoietic stem cells and alternative model systems for nanoparticle discovery
Abstract:
Lipid nanoparticles (LNPs) have been used to deliver RNA in several FDA-approved drugs, including treatments for genetic liver diseases (e.g., ONPATRO) and COVID-19 vaccines (e.g., SPIKEVAX, COMIRNATY). The current LNP discovery pipeline selects nanoparticles with high liver biodistribution, but development of next generation RNA therapies will require LNPs that de-target the liver and deliver RNA to therapeutically relevant cell types. Hematopoietic stem cells (HSCs) represent one such cell type as their dysfunction drives pathologies including sickle cell disease, ß-thalassemia, anemias, immunodeficiencies, and metabolic disorders. In this work, I use high-throughput LNP screening techniques to identify LNPs with desirable HSC tropism, while investigating key barriers to clinical translation. In Aim 1, I identify lead candidate HSC-LNPs from an LNP library using high-throughput screening at single-cell resolution. Candidate LNPs are evaluated for their physical characteristics and in vivo delivery profiles. In aim 2, a lead candidate HSC-LNP is evaluated in different pre-clinical models including ex vivo primary human CD34+ cells and nonhuman primates. Aim 3 proposes an alternative model system in the nanoparticle discovery pipeline by evaluating delivery differences from an LNP library in cohorts of healthy primates and those with idiopathic chronic diarrhea (ICD). Developing LNPs with favorable delivery profiles to HSCs could unlock treatments for a multitude of blood disorders, while investigating alternative models in the nanoparticle discovery pipeline may improve the speed and efficiency at which clinically translatable, non-liver LNPs are identified.
