Cited by 142RNA Interference and Gene DeliveryBarrier Structure and Function StudiesDrug Transport and Resistance Mechanisms

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

Barker, Scarlett J., Thayer, Mai B., Kim, Chaeyoung, Tatarakis, David, Simon, Matthew J., Dial, Rebekah, Nilewski, Lizanne, Wells, Robert C. +38 more·2024·Science Translational Medicine

Abstract

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, neurons, astrocytes, microglia, and oligodendrocytes. In addition, systemic delivery of OTV enabled Malat1 RNA knockdown in mouse quadriceps and cardiac muscles, which are difficult to target with oligonucleotides alone. Systemically delivered OTV enabled a more uniform ASO biodistribution profile in the CNS of TfR mu/hu KI mice and greater knockdown of Malat1 RNA compared with a bivalent, high-affinity TfR antibody. In cynomolgus macaques, an OTV directed against MALAT1 displayed robust ASO delivery to the primate CNS and enabled more uniform biodistribution and RNA target knockdown compared with intrathecal dosing of the same unconjugated ASO. Our data support systemically delivered OTV as a potential platform for delivering therapeutic ASOs across the BBB.

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Crossref · 10.1126/scitranslmed.adi2245

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Authors
Barker, S. J., Thayer, M. B., Kim, C., Tatarakis, D., Simon, M. J., Dial, R., Nilewski, L., Wells, R. C., Zhou, Y., Afetian, M., Akkapeddi, P., Chappell, A., Chew, K. S., Chow, J., Clemens, A., Discenza, C. B., Dugas, J. C., Dwyer, C., Earr, T., Ha, C., Ho, Y. S., Huynh, D., Lozano, E. I., Jayaraman, S., Kwan, W., Mahon, C., Pizzo, M., Robles-Colmenares, Y., Roche, E., Sanders, L., Stergioulis, A., Tong, R., Tran, H., Zuchero, Y., Estrada, A. A., Gadkar, K., Koth, C. M. M., Sanchez, P. E., Thorne, R. G., Watts, R. J., Sandmann, T., Kane, L. A., Rigo, F., Dennis, M. S., Lewcock, J. W., & DeVos, S. L.
Affiliations
  • Denali Therapeutics (United States) (US)
  • Ionis Pharmaceuticals (United States) (US)
  • Denali Therapeutics Inc., South San Francisco, CA, USA.
Corresponding author
  • Barker, Scarlett J.
  • Thayer, Mai B.
  • Kim, Chaeyoung
  • Tatarakis, David
Venue
Science Translational Medicine
Published
2024-08-14
Volume
16
Issue
760
Pages
eadi2245-eadi2245
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
OpenAlex
W4401596729
Cited by
142
References
70
Citations by year
2026: 65 · 2025: 68 · 2024: 8 · 2023: 1
FWCI
19.19
Type
journal article
Language
en
Open access
closed
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords
antisense oligonucleotides, blood-brain barrier, transferrin receptor 1, MALAT1, brain drug delivery, systemic drug delivery, cynomolgus macaques, RNA knockdown, intrathecal drug delivery, tissue distribution
MeSH terms
Animals, Biological Transport, Blood-Brain Barrier, Humans, Macaca fascicularis, Receptors, Transferrin, Tissue Distribution, Oligonucleotides, Antisense, Mice, Gene Knockdown Techniques, RNA, Long Noncoding

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