Prakash Thazha P, Lima Walt F, Murray Heather M, Elbashir Sayda, Cantley William, Foster Don, Jayaraman Muthusamy, Chappell Alfred E, Manoharan Muthiah, Swayze Eric E, Crooke Stanley T
Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc. , 1896 Rutherford Road, Carlsbad, California 92008, United States.
ACS Chem Biol. 2013 Jul 19;8(7):1402-6. doi: 10.1021/cb4001316. Epub 2013 May 2.
We evaluated the abilities of an antisense oligonucleotide (ASO), a small interfering RNA (siRNA), and a single-stranded siRNA (ss-siRNA) to inhibit expression from the PTEN gene in mice when formulated identically with lipid nanoparticles (LNPs). Significantly greater reductions in levels of PTEN mRNA were observed for LNP-formulated agents compared to unformulated drugs when gene silencing was evaluated after a single dose in the livers of mice. An unformulated ss-siRNA modified with a metabolically stable phosphate mimic 5'-(E)-vinylphosphonate showed dose-dependent reduction of PTEN mRNA in mice, albeit at doses significantly higher than those observed for formulated ss-siRNA. These results demonstrate that LNPs can be used to deliver functional antisense and ss-siRNA therapeutics to the liver, indicating that progress in the field of siRNA delivery is transferable to other classes of nucleic acid-based drugs.
我们评估了反义寡核苷酸（ASO）、小干扰RNA（siRNA）和单链siRNA（ss-siRNA）在与脂质纳米颗粒（LNP）相同配方时抑制小鼠PTEN基因表达的能力。当在小鼠肝脏中单次给药后评估基因沉默时，与未配方化的药物相比，观察到LNP配方化的药物使PTEN mRNA水平显著降低。用代谢稳定的磷酸模拟物5'-（E）-乙烯基膦酸修饰的未配方化的ss-siRNA在小鼠中显示出PTEN mRNA的剂量依赖性降低，尽管其剂量明显高于配方化的ss-siRNA所观察到的剂量。这些结果表明，LNP可用于将功能性反义核酸和ss-siRNA疗法递送至肝脏，这表明siRNA递送领域的进展可转移至其他基于核酸的药物类别。
