Intravenous administration of blood-brain barrier-crossing conjugates facilitate biomacromolecule transport into central nervous system

  • Nat Biotechnol. 2024 Nov 25. doi: 10.1038/s41587-024-02487-7.
Chang Wang  #  1  2  3  4  5  6  7 ,  Siyu Wang  #  1  2  3  4  5  6  7 ,  Yonger Xue  1  2  3  4  5  6  7 ,  Yichen Zhong  1  2  3  4  5  6  7 ,  Haoyuan Li  1  2  3  4  5  6  7 ,  Xucheng Hou  1  2  3  4  5  6  7 ,  Diana D Kang  1  2  3  4  5  6  7  8 ,  Zhengwei Liu  1  2  3  4  5  6  7 ,  Meng Tian  1  2  3  4  5  6  7 ,  Leiming Wang  1  2  3  4  5  6  7 ,  Dinglingge Cao  1  2  3  4  5  6  7 ,  Yang Yu  8 ,  Jayce Liu  8 ,  Xiaolin Cheng  8  9 ,  Tamara Markovic  6  10 ,  Alice Hashemi  11 ,  Brian H Kopell  11 ,  Alexander W Charney  11 ,  Eric J Nestler  12  13 ,  Yizhou Dong  14  15  16  17  18  19  20
Affiliations
  • 1. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 2. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 3. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 6. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 7. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 8. College of Pharmacy, The Ohio State University, Columbus, Columbus, OH, USA.
  • 9. Translational Data Analytics Institute, The Ohio State University, Columbus, OH, USA.
  • 10. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 11. Charles Bronfman Institute for Personalized Medicine, Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 12. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 13. Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 14. Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 15. Marc and Jennifer Lipschultz Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 16. Department of Immunology and Immunotherapy, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 17. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 18. The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 19. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • 20. Biomedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  • # Contributed equally.
PMID: 39587229 DOI: 10.1038/s41587-024-02487-7
Abstract

Delivery of biomacromolecules to the central nervous system (CNS) remains challenging because of the restrictive nature of the blood-brain barrier (BBB). We developed a BBB-crossing conjugate (BCC) system that facilitates delivery into the CNS through γ-secretase-mediated transcytosis. Intravenous administration of a BCC10-oligonucleotide conjugate demonstrated effective transportation of the oligonucleotide across the BBB and gene silencing in wild-type mice, human brain tissues and an Amyotrophic Lateral Sclerosis mouse model.

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