Sebastian Huayamares

BME PhD Proposal Presentation

Date: 2023-01-31
Time: 2:00pm
Location / Meeting Link: Children's Healthcare of Atlanta Seminar Room, EBB / https://emory.zoom.us/j/6851219755

Committee Members:
James E. Dahlman, Ph.D. (Advisor); Eric J. Sorscher, M.D.; Philip J. Santangelo, Ph.D.; Kyle R. Allison, Ph.D.; Wilbur A. Lam, M.D., Ph.D.


Title: Translational design of lipid nanoparticles (LNPs) to deliver mRNA therapies to solid tumors and the lungs

Abstract:
Lipid nanoparticles (LNPs) are a clinically relevant way to deliver therapeutic mRNA in patients. Major milestones for LNP-RNA drugs include the Food and Drug Administration (FDA) approval of Alnylam’s ONPATTRO® in 2018 for treating liver genetic disease following systemic administration as well as Moderna’s SPIKEVAX® and Pfizer-BioNTech’s COMIRNATY® unprecedentedly fast Emergency Use Approval (EUA) in 2020 for vaccination against COVID-19. Despite the success of this novel class of therapies for rare genetic diseases in the liver and respiratory infectious diseases, the full potential of LNP-RNA drugs for other indications is still being unveiled. LNP-RNA drugs to treat solid tumors are yet to be approved but highly anticipated, given that oncology has consistently been the dominant indication among new FDA approvals and investigational therapies in clinical development for the past five years. In this work, I propose to improve mRNA delivery to solid tumors through systemic and localized administration. As part of my first aim, I will use high-throughput LNP screening assays to identify an LNP that can functionally deliver mRNA to head and neck squamous cell carcinoma (HNSCC) solid tumors in vivo while minimizing off-target delivery to the liver. For my second aim, I will investigate the intratumoral delivery of mRNA using LNPs. Using stereo-pure and scalable ionizable lipids, I will formulate and screen LNPs administered intratumorally. The best-performing LNP will then be used to deliver purine nucleoside phosphorylase (PNP)-encoding mRNA intratumorally. In combination with fludarabine phosphate as a prodrug, this will elicit a cytoreductive effect that will result in regression of patient-derived xenograft (PDX) HNSCC solid tumors in vivo. Additionally, I will study mRNA delivery to solid tumors on a multi-omic level using single-cell RNA sequencing (scRNAseq) to identify pathways and genes that can be harnessed therapeutically. Finally, for my third aim, I will design translational, clinically relevant LNPs to deliver therapeutic mRNA via nebulization for respiratory diseases. The nebulization process exerts strains on LNP-mRNA drugs that reduce mRNA functional expression, which may have caused Translate Bio’s nebulized LNP-mRNA drug candidate to fail at improving lung function in cystic fibrosis patients during their Phase I-II clinical trial in 2021. Here, I will identify LNPs that can enhance functional delivery of mRNA via nebulization while keeping them simple, scalable, and patentable.