Ionizable Lipid Nanoparticles for Therapeutic Base Editing of Congenital Brain Disease.

Abstract

Delivery of mRNA-based therapeutics to the perinatal brain holds great potential in treating congenital brain diseases. However, nonviral delivery platforms that facilitate nucleic acid delivery in this environment have yet to be rigorously studied. Here, we screen a diverse library of ionizable lipid nanoparticles (LNPs) via intracerebroventricular (ICV) injection in both fetal and neonatal mice and identify an LNP formulation with greater functional mRNA delivery in the perinatal brain than an FDA-approved industry standard LNP. Following <i>in vitro</i> optimization of the top-performing LNP (C3 LNP) for codelivery of an adenine base editing platform, we improve the biochemical phenotype of a lysosomal storage disease in the neonatal mouse brain, exhibit proof-of-principle mRNA brain transfection <i>in vivo</i> in a fetal nonhuman primate model, and demonstrate the translational potential of C3 LNPs <i>ex vivo</i> in human patient-derived brain tissues. These LNPs may provide a clinically translatable platform for <i>in utero</i> and postnatal mRNA therapies including gene editing in the brain.