Sebastian Huayamares
BME PhD Defense Presentation

Date: 2023-12-06
Time: 1:00 PM-2:00 PM
Location / Meeting Link: HSRB-II N600 Conference Room / https://emory.zoom.us/j/6851219755

Committee Members:
James Dahlman, PhD (Advisor); Eric Sorscher, MD; Philip Santangelo, PhD; Kyle Allison, PhD; Wilbur Lam, MD, PhD


Title: Translational design of lipid nanoparticles (LNPs) to deliver mRNA therapies to solid tumors and to 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 the unprecedentedly fast Emergency Use Approval (EUA) of Moderna’s SPIKEVAX® and Pfizer-BioNTech’s COMIRNATY® 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 sought to improve mRNA delivery to solid tumors through systemic and localized administration. As part of my first aim, I used high-throughput LNP screening assays to identify an LNP that can functionally deliver mRNA to human head and neck squamous cell carcinoma (HNSCC) solid tumors in vivo while minimizing off-target delivery to the liver. For my second aim, I investigated the intratumoral delivery of mRNA via LNPs. Using stereo-pure and scalable ionizable lipids, I formulated and screened LNPs administered intratumorally. The best-performing LNP was then used to deliver purine nucleoside phosphorylase (PNP)-encoding mRNA intratumorally. In combination with fludarabine phosphate as a prodrug, this elicited cytoreductive anti-tumor effects that resulted in regression of patient-derived xenograft (PDX) HNSCC solid tumors in vivo. Additionally, I studied mRNA delivery to solid tumors on a multi-omic level using single-cell RNA sequencing (scRNA-seq) and identified pathways and upregulated genes related to this therapeutic modality. Finally, for my third aim, I designed translational, clinically relevant LNPs to deliver therapeutic mRNA to the respiratory airway via nebulization. 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 engineered LNPs for enhanced functional delivery of mRNA via nebulization while keeping them translationally relevant. These improved LNPs were then used to deliver a therapeutically relevant mRNA cargo to develop an LNP-mRNA therapy for the treatment of pulmonary alveolar proteinosis.