Targeting Transferrin Receptor to Transport Antisense Oligonucleotides Across the Blood-Brain Barrier

Author:

Barker Scarlett JORCID,Thayer Mai BORCID,Kim Chaeyoung,Tatarakis David,Simon Matthew,Dial Rebekah L,Nilewski Lizanne,Wells Robert C,Zhou Yinhan,Afetian Megan,Chappell Alfred,Chew Kylie S,Chow Johann,Clemens Allisa,Discenza Claire B,Dugas Jason,Dwyer Chrissa,Earr Timothy,Ha Connie,Huynh David,Jayaraman Srini,Kwan Wanda,Mahon Cathal,Pizzo Michelle,Roche Elysia,Sanders Laura,Stergioulis Alexander,Tong Raymond,Tran Hai,Zuchero Joy,Estrada Anthony A,Gadkar Kapil,Koth Christopher MM,Sanchez Pascal E,Thorne Robert G,Watts Ryan J,Sandmann Thomas,Kane Lesley,Rigo Frank,Dennis Mark S,Lewcock Joseph W,DeVos Sarah LORCID

Abstract

AbstractAntisense oligonucleotides (ASO) are promising therapies for neurological disorders, though they are unable to cross the blood-brain barrier (BBB) and must be delivered directly to the central nervous system (CNS). Here, we use a human transferrin receptor (TfR)-binding molecule to transport ASO across the BBB in mice and non-human primates, termed oligonucleotide transport vehicle (OTV). Systemically delivered OTV drives significant, cumulative, and sustained knockdown of the ASO target across multiple CNS regions and all major cell types. Further, systemic OTV delivery enables more uniform ASO biodistribution and knockdown compared to two other clinically relevant ASO delivery routes: a standard, high affinity TfR antibody, or direct ASO delivery to the CSF. Together, our data support systemically delivered OTV as a potential therapeutic platform for neurological disorders.One-Sentence SummarySystemically dosed OTV delivered via TfR1 targeting shows widespread and cumulative target knockdown in the mouse and NHP CNS.

Publisher

Cold Spring Harbor Laboratory

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