Targeting the transferrin receptor to transport antisense oligonucleotides across the mammalian blood-brain barrier

Antisense oligonucleotides (ASOs) are promising therapeutics for treating various neurological disorders. However, ASOs are unable to readily cross the mammalian blood-brain barrier (BBB) and therefore need to be delivered intrathecally to the central nervous system (CNS). Here, we engineered a human transferrin receptor 1 (TfR1) binding molecule, the oligonucleotide transport vehicle (OTV), to transport a tool ASO across the BBB in human TfR knockin (TfR mu/hu KI) mice and nonhuman primates. Intravenous injection and systemic delivery of OTV to TfR mu/hu KI mice resulted in sustained knockdown of the ASO target RNA, Malat1 , across multiple mouse CNS regions and cell types, including endothelial cells,…