Lipid nanoparticle delivery limits antisense oligonucleotide activity and cellular distribution in the brain after intracerebroventricular injection
Amy E. Byrnes, Sara L. Domínguez, Chun‐Wan Yen, Benjamin I. Laufer, Oded Foreman, Mike Reichelt, Han Lin, Meredith Sagolla, Kathy Hötzel, Hai Ngu, Christoffer Soendergaard, Alberto Estevez, Hsiu-Chao Lin, Alexandre Goyon, Juan Bian, Jessica Lin, Flora I. Hinz, Brad A. Friedman, Amy Easton, Casper C. Hoogenraad
Abstract
, LNP-delivered ASOs did not downregulate mRNA levels throughout the brain after intracerebroventricular injection. This lack of activity was likely due to ASO accumulation in cells lining the ventricles and blood vessels. Furthermore, we reveal a formulation-dependent activation of the immune system post dosing, suggesting that LNP encapsulation cannot mask cellular ASO backbone-mediated toxicities. Together, these data provide insights into how LNP encapsulation affects ASO distribution as well as activity in the brain, and a foundation that enables future optimization of brain-targeting ASO-LNPs.