Ligand Conjugated Multimeric siRNAs Enable Enhanced Uptake and Multiplexed Gene Silencing
| Autor: | Hans-Peter Vornlocher, Brown Jonathan Miles, Monika Krampert, James E. Dahlman, Kristin K.H. Neuman, Carla Alexandra Hernandez Prata, Philipp Hadwiger |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
oligonucleotide
0301 basic medicine Small interfering RNA Acetylgalactosamine Oligonucleotides enhanced Conjugated system Ligands TTR Biochemistry 03 medical and health sciences 0302 clinical medicine In vivo Drug Discovery Genetics Humans Gene silencing Gene Silencing RNA Small Interfering Molecular Biology RNA Double-Stranded Gene knockdown multimer Ligand Oligonucleotide Chemistry knockdown Biological Transport Genetic Therapy Original Papers GalNAc Cell biology 030104 developmental biology 030220 oncology & carcinogenesis Hepatocytes Molecular Medicine Conjugate |
| Zdroj: | Nucleic Acid Therapeutics |
| ISSN: | 2159-3345 2159-3337 |
| Popis: | Small interfering RNAs (siRNAs) conjugated to N-acetylgalactosamine (GalNAc) ligands have been used to treat disease in patients. However, conjugates with other ligands deliver siRNA less efficiently, limiting the development of new targeted therapies. Most approaches to enhancing the potency of such conjugates have concentrated on increasing ligand effectiveness and/or the chemical stability of the siRNA drug. One complementary and unexplored alternative is to increase the number of siRNAs delivered per ligand. An ideal system would be a single chemical entity capable of delivering multiple copies of an oligonucleotide drug and/or several such drugs simultaneously. Here we report that siRNAs can be stably linked together under neutral aqueous conditions to form chemically defined siRNA “multimers,” and that these multimers can be delivered in vivo by a GalNAc ligand. Conjugates containing multiple copies of the same siRNA showed enhanced activity per unit of ligand, whereas siRNAs targeting different genes linked to a single ligand facilitated multigene silencing in vivo; this is the first demonstration of silencing several genes simultaneously in vivo using ligand-directed multimeric siRNA. Multimeric oligonucleotides represent a powerful and practical new approach to improve intracellular conjugate delivery. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|