Advanced tools for translation of intravenously-infused RNA LNP therapeutics to the clinic - Abstract Rejuvenation Technologies Inc. (RTI) seeks to improve the tools required for clinical translation of intravenously- infused RNA lipid nanoparticle (LNP) therapeutics. While there is abundant work on RNA LNP vaccines, the requirements for intravenously-infused LNPs are significantly more demanding, because instead of causing an immune response as with a vaccine, IV-infused LNPs must avoid an immune response. Immune responses can be caused by the RNA or the LNP components, and can lead to adaptive immunity, autoimmunity, anaphylactic shock, desensitization or sensitization, and reduced drug potency with repeat dosing. As a test case, RTI will focus on their telomere extension biologic, which has shown highly successful proof-of-concept rescue of multiple mouse models of liver and lung disease. Telomeres are the protective DNA tips of chromosomes. Telomeres shorten with each cell division, eventually exposing the DNA tip, causing genome instability and progenitor cell apoptosis or senescence. This diminishes the regenerative capacity of organs, driving a number of pathological conditions that include aging-related diseases like lung, kidney, and liver fibrosis, and bone marrow failure. Thus, telomere extension represents a promising strategy for regenerative medicine. RTI’s solution is to extend critically short telomeres by transiently increasing TERT levels via targeted delivery of modified TERT mRNA in biodegradable lipid nanoparticles (LNPs). RTI has multiple LNPs capable of delivering mRNA to the lung or liver with world- leading efficiency, transfecting >90% of target cells, even in diseased organs. Upon delivery to cells, TERT mRNA is translated to functional TERT protein, and both are degraded within days, yet telomeres are extended sufficiently to reverse years of shortening. Preliminary work has shown the strong potential benefits of the TERT therapy in models of both liver and lung fibrosis. Moreover, RTI has developed broadly transfecting-LNPs capable of transfecting 16 tissues in non-human primates, opening the door to extra-hepatic extra-pulmonary mRNA delivery. In the future, RTI intends to add targeting ligands, conferring additional cell type-specificity and enabling the extension of these results to other forms of disease. In this Direct to Phase II project, RTI seeks to develop a platform that can be used for efficient translation and manufacturing following FDA’s chemistry, manufacturing, and controls guidelines of TERT mRNA LNP therapies from preclinical models to the clinic. To do so, RTI will undertake four specific aims: 1) high-sensitivity drug- specific analytical capability development, 2) high-sensitivity cell-type-specific biodistribution, 3) evaluating drug component stability, and 4) high-sensitivity bioanalytical methods for identifying drug breakdown products. These studies will provide the high-sensitivity methods critical for clinical translation of intravenously-infused RNA LNP therapeutic drug products. As a specific use case, these studies will support translation of RTI’s TERT mRNA LNPs for multiple clinical indications with dire unmet medical need.
