(T1530-12-82) Well Characterized Lipid Nanoparticle Library Accelerates Development of Next Generation Genomic Medicines

Purpose: Ionizable amino lipids are a major constituent of the lipid nanoparticles for delivering nucleic acid therapeutics (e.g., DLin-MC3-DMA in ONPATTRO®, ALC-0315 in Comirnaty®, SM-102 in Spikevax®). Scarcity of lipids that are suitable for cell therapy, vaccination, and gene therapies continue to be a problem in advancing many potential diagnostic/therapeutic/vaccine candidates to the clinic. Herein, we describe the development of novel ionizable lipids to be used as functional excipients for designing vehicles for nucleic acid therapeutics/vaccines in vivo or ex vivo use in cell therapy applications.

Methods: We studied the transfection efficiency (TE) of LNP-based mRNA formulations of novel ionizable lipid candidates in primary human T cells and established a workflow for engineering of primary immune T cells towards non-viral CAR T therapy. Lipids were also tested in rodents for vaccine applications using self-amplifying RNA (saRNA) encoding various antigens. We have then evaluated safety and efficacy of various ionizable lipid candidates and their biodistribution using various LNP compositions. Further, using ionizable lipids from the library, we have shown gene editing of various targets in rodents.

Results: Proprietary ionizable lipids and novel LNP compositions showed very high TE over MC3- LNPs in primary human T cells. Following IV administration of human erythropoietin (EPO) mRNA encoded LNPs, human EPO was generated resulting in an increase in hematocrit. Proprietary lipids comprising LNP vaccine candidates using self-amlifying RNA encoded for SARS-CoV-2 spike protein showed IgG levels specific to spike protein. The IgG levels were comparable to to that of SM-102 and ALC-0315 lipids used in the current mRNA vaccines. Preliminay results show case gene knock out of transthyretin and PCSK9 proein. Finally, We were able to show that physico-chemical profiles of ionizable lipids are going to be different for cell therapy, protein replacement, gene editing and vaccine applications.

Conclusion: PNI proprietary lipid and or LNP compositional library can be used to mitigate the challenges in genomics medicine development by plug and play nature of the technology. We believe that these studies will pave the path to the advancement in nucleic acid based therapeutics and vaccines, or for cell & gene therapy agents for early diagnosis and detection of cancer, and for targeted genomic medicines.