Sebastian Rudden
BME PhD Proposal Presentation

Date: 2025-09-16
Time: 10:00 am - 12:00 pm EST
Location / Meeting Link: HSRB II, N600
Committee Members:
James Dahlman, PhD (Advisor); Brandon Dixon, PhD; Hanjoong Jo, PhD; Yonggang Ke, PhD; Hyejin Kim, PhD


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 mRNA, 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 aim 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. If in vivo CAR continues to work, it has the potential to once again revolutionize not just CAR therapy, but cancer treatment at large. This is no exaggeration - last month, AbbVie acquired an in vivo CAR company (using LNPs) for $2 billion. We believe that by using our potent LNPs combined with advanced preclinical models, we can substantially support in vivo CAR efforts, thereby helping to make this lifesaving therapy more accessible. To this end, I will share preliminary data showing that LNP27 can generate CAR in mice in vivo and in NHP spleen cells ex vivo, and propose how we will use LNP27 to generate in vivo panCAR (all immune cells activated and ready to fight cancer) in end-of-life NHPs to produce a therapeutic effect.