Sebastian Rudden
BME PhD Defense Presentation

Date: 2026-11-06
Time: 8:00 AM EST
Location / Meeting Link: HSRB II, N600 https://emory.zoom.us/j/99390112284?pwd=0kw1VXHA4qUm8rnbkn1s56TmP49LIF.1

Committee Members:
James Dahlman, Ph.D. (Advisor); Brandon Dixon, Ph.D.; Hanjoong Jo, Ph.D.; Yonggang Ke, Ph.D.; Hyejin Kim, Ph.D.


Title: A Novel Amino Lipid Series for mRNA Delivery, validated in pseudo-clinical trials

Abstract:
Lipid nanoparticles (LNPs) are the most clinically advanced delivery method for RNA, which has the potential to treat myriad diseases. There is an ongoing need for novel lipids which are highly potent, safe, and minimize off-target delivery. First, I will walk through how we screened dozens of chemically distinct ionizable lipids (which are the heart of LNPs) to obtain a lipid class which meets all these criteria. Next, I will demonstrate extensive mouse validation showing that our lead LNP27 is 10x more potent than Moderna’s vaccine LNP, while maintaining an excellent on/off target ratio and safety profile. We finally demonstrate functional delivery of a reporter protein in non-human primates (NHPs) at a low dose. This pseudo-clinical trial approach minimizes loss of life by using NHPs that are already scheduled for euthanasia due to chronic illness. Having validated LNP27 thoroughly, I next aimed to examine how it can deliver a therapeutic cargo. CAR T therapy has revolutionized cancer treatment, saving the lives of many relapsed patients who otherwise had a bleak prognosis. However the current standard-of-care involves immense cost (~$0.5 million) and other challenges. LNPs have the potential to facilitate in vivo CAR therapy, bypassing many of these challenges and potentially making this lifesaving option more accessible. If in vivo CAR continues to work, it has the potential to once again revolutionize not just CAR therapy, but cancer treatment at large. As one of many examples: Orna, a start-up company using ligand-free LNPs to generate in vivo CAR, was acquired for $2.4 billion this February. In parallel to these translationally-focused tracks, I also used one of these novel lipids to probe more fundamental questions of how LNP design affects stability and immunogenicity, curious how the design rules and dogmas established by/for earlier generations of LNPs apply today. In summary, this thesis will expose the design and validation process of a novel class of LNPs, explore their potential for therapeutic application, and examine how they interplay with widely-held beliefs in the field.