Clinically-useful vehicles for in vivo delivery of mRNA to stem and progenitor cells - Abstract Rejuvenation Technologies Inc. (RTI) aims to expand the utility of our telomere extension biologic, telomerase (TERT) mRNA, and our world-leading lipid nanoparticle (LNP) delivery vehicle by adding progenitor cell (PC) targeting capability. Telomeres are the protective DNA tips of chromosomes essential for cell and lung health. Telomeres shorten with each cell division, eventually exposing the DNA tip, which is detected as broken DNA, with multiple deleterious consequences, many of which are known features of a number of diseases, such as loss of progenitor cells, cellular senescence, secretion of molecules that activate fibroblasts, altered gene expression, fibrosis, organ failure, and death. Critically short telomeres also drive further telomere shortening in a vicious cycle. By targeting TERT mRNA to PCs, we can extend the regenerative capacity of these cells, mitigating this vicious cycle and extending the healthspan. There is an unmet medical need for vehicles to deliver therapeutic mRNA to PCs, the primary cells of regenerative medicine. PC-targeting vehicles could deliver mRNA encoding any gene to PCs, fostering a new era of regenerative medicine. RTI has achieved a breakthrough in mRNA delivery with the development of a novel, broadly-transfecting (BT)-LNP formulation. BT-LNPs have been shown to transfect 16 tissues in non-human primates (NHPs), making them the only LNPs capable of transfecting such a broad range of tissues to our knowledge. BT-LNPs are also well-tolerated in multiple species including NHPs. RTI’s BT-LNP formulation can serve as a “base LNP” for targeting ligand attachment, conferring additional cell type-specificity. By combining this with our TERT mRNA, which has shown highly successful rescue in mouse models of both pulmonary and liver fibrosis, we seek to extend the regenerative capacity of various PC types, addressing multiple disease indications. In this Phase I project, RTI will add PC targeting capability to our BT-LNPs using the following approach: 1) Generate a library of rationally designed peptides targeting three PC types. 2) Utilize a computational structural biology pipeline to screen candidate peptide targeting ligands in silico. 3) Add the candidate targeting ligands to our broadly-transfecting base vehicle BT-LNPs. 4) Perform an efficient, sensitive in vivo screen to quantify the ability of each candidate LNP to transfect each of the 3 PC types. This Phase I project will produce highly efficient, well-tolerated vehicles for in vivo delivery of mRNA to three PC types, as well as a platform for efficient development of additional vehicles. This will both advance our novel telomere extension biologic for multiple indications and allow us to pursue out-licensing for the CVs to potential pharma and biotech partners.
