Development of novel lipid nanoparticles for nucleic acids delivery in the brain

PROJECT SUMMARY Lipid nanoparticles (LNPs) are a promising delivery method for nucleic acid-based therapeutics in the brain. LNPs are composed of ionizable lipids and helper components, which are biocompatible and biodegradable, and can protect RNA from degradation and improve its stability. Additionally, LNPs can be engineered to cross the blood-brain barrier (BBB) and deliver nucleic acids to brain cells, including neuronal populations that are implicated in neurological and psychiatric disorders. Particularly, amino acid and glucose transporters that play critical roles in molecular trafficking have been explored for nucleic acid delivery in multiple animal models. Preclinical data demonstrate the importance of both LNP formulations and these cell surface receptors for effectively crossing the BBB. Despite these important findings, effective and safe delivery of nucleic acids to various cell types in the brain remains a significant challenge in the delivery field. To overcome these challenges, we propose to integrate BBB-crossing lipid nanoparticles (BLNPs) and engineered nucleic acids for brain cell delivery. In preliminary studies, we developed several classes of BLNPs, which showed great potential to cross the BBB and deliver mRNAs into the mouse brain. Moreover, we constructed mRNAs to include specific sequences that lead to their de-targeting to mouse liver. Based on these results, the goal of this proposed project is to develop BBB-crossing lipid nanoparticles (BLNPs) as functional nanomaterials capable of efficiently delivering nucleic acids in vivo, consequently generating strong functions such as gene silencing or protein expression. The following specific aims will be carried out to accomplish our goal: 1) To synthesize and characterize BBB-crossing lipid nanoparticles (BLNPs); 2) To identify lead BLNPs and elucidate their trafficking pathways in mouse models; and 3) To determine delivery efficiency and safety profiles of BLNPs in mouse and non-human primate (NHP) models. The teams at the Icahn School of Medicine at Mount Sinai (ISMMS) and Biogen Inc. will work closely on the discovery and development of the delivery platform that can potentially be applied to several therapeutic indications. We anticipate, if successful, that this project will greatly expand the knowledge for brain delivery and advance nucleic acid-based therapeutics. Multiple early-stage clinical trials will be initiated within the coming decade for the treatment of many common and severe neurological and psychiatric disorders.