Therapeutic effects of APOE regulation via LNP-RNA formulations in Alzheimer's disease

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Abstract

PROJECT SUMMARY Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions worldwide, characterized by memory loss and cognitive decline. The Apolipoprotein E (ApoE) gene is closely linked to AD risk, with APOE4 associated increased susceptibility while APOE2 exhibits protective effects, although the mechanisms of this protection remain poorly understood. Nucleic acid-based therapeutics offer promising avenues for treating AD by targeting pathological genes like APOE and promoting therapeutic protein expression. However, their efficacy is hindered by challenges in crossing the blood-brain barrier (BBB). To address this, we aim to develop novel lipid nanoparticles (LNPs) designed to interact with specific BBB-related receptors for efficient delivery of nucleic acids to the brain. Our objectives include synthesizing novel BBB-crossing lipids (BLs), formulating a library of LNPs, and elucidating their trafficking pathways across the BBB. Additionally, we will engineer siRNA and mRNA sequences to modulate APOE4 and APOE2 expression, optimizing their design and assessing their potency. Lastly, we will evaluate the therapeutic effects, pharmacokinetics, and safety of LNP- RNA formulations in mouse AD models, including examination of brain delivery using PET/MRI imaging. This comprehensive approach aims to advance our understanding of AD pathogenesis and develop innovative therapies targeting APOE for the treatment of this debilitating disease.