Systemic mRNA-LNP administration in fetuses improves survival in a mouse model of spinal muscular atrophy.

Base editing provides a unique opportunity for the permanent correction of central nervous system (CNS) diseases with early onset pathology. While lipid nanoparticles (LNPs) have emerged as an effective messenger RNA (mRNA) delivery system for liver base editing, extrahepatic delivery of base editing components to the CNS is poor. To identify CNS-penetrant LNPs, we profiled cell-type-specific mRNA-LNP delivery across developmental stages in the liver and CNS. We identified one LNP (LNP1) with efficient mRNA delivery to endothelial cells, microglia, and neurons in the cortex of fetal recipients. We then applied these findings to spinal muscular atrophy (SMA) and systemically delivered LNP1, encapsulating adenine base editor mRNA and a therapeutic single guide RNA (gRNA) for the upregulation of survival of motor neuron 2 (SMN2) in a humanized severe mouse model of SMA. We demonstrated base editing in the liver and the cortex. Despite low levels of editing in CNS organs, fetal administration modestly increased survival in SMA mice, providing a foundation for a fetal base editing approach for SMA. In conclusion, we leverage our discovery related to basic fetal biology and its influences on mRNA-LNP delivery to develop clinically relevant CNS therapies.