Multimeric small interfering ribonucleic acid for highly efficient sequence-specific gene silencing.
Small interfering RNA (siRNA) with 19-21 base pairs has been recently recognized as a new therapeutic agent for effectively silencing a specific gene on a post-transcription level. For siRNA therapeutics, safe and efficient delivery issues are significant hurdles to clinical applications. Here we present a new class of biologically active siRNA structure based on chemically self-crosslinked and multimerized siRNA through cleavable disulphide linkages. The multimerized siRNA can produce more stable and compact polyelectrolyte complexes with less cytotoxic cationic carriers than naked siRNA because of substantially increased charge densities and the presence of flexible chemical linkers in the backbone. The cleavable and multimerized siRNA shows greatly enhanced gene-silencing efficiencies in vitro and in vivo through a target-messenger-RNA-specific RNA interference processing without significantly eliciting immune induction. This study demonstrates that the multimerized siRNA structure complexed with selected cationic condensing agents can serve as potential gene-silencing therapeutics for treating various diseases.
Mok
Hyejung
H
Department of Biological Sciences and Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, South Korea.
Lee
Soo Hyeon
SH
Park
Ji Won
JW
Park
Tae Gwan
TG
D004591:Electrophoresis, Polyacrylamide Gel; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000235:genetics; D009690:Nucleic Acid Conformation; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D049452:Green Fluorescent Proteins