Our aim was to explore the pharmacodynamics and biodistribution of spherical nucleic acids (SNAs^™) in human neurons (iNs) and in the mouse, rat, and nonhuman primate (NHP) central nervous system (CNS).

SNAs are densely packed oligonucleotides radially arranged around a nanoparticle core. Prior work indicates that: i) SNAs show increased cellular uptake and target affinity compared with their linear counterparts, ii) the splice-switching oligonucleotide nusinersen formulated into SNA (nusinersen-SNA) improves survival of spinal muscular atrophy (SMA) mice following intracerebroventricular injection, and iii) intrathecally delivered nusinersen-SNA shows improved biodistribution throughout the rat CNS relative to nusinersen. We hypothesized that the SNA-mediated increased survival was due, in part, to improved pharmacodynamics and persistence in target tissues.