Musculoskeletal Research Laboratory, Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.
Nat Med. 2012 Jan 29;18(2):307-14. doi: 10.1038/nm.2617.
Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.
代谢性骨骼疾病与骨形成受损有关，是一个主要的临床挑战。一种治疗这些缺陷的方法是通过小干扰 RNA（siRNA）沉默成骨细胞系细胞中抑制骨形成的基因，这些细胞占据了骨形成表面周围的龛位。我们开发了一种靶向系统，涉及二油酰基三甲基铵丙烷（DOTAP）为基础的阳离子脂质体连接到六个重复的天冬氨酸、丝氨酸、丝氨酸序列（AspSerSer）（6），用于将 siRNA 特异性递送到骨形成表面。使用该系统，我们封装了一种针对酪蛋白激酶-2 相互作用蛋白 1（由 Plekho1 编码，也称为 Plekho1）的成骨 siRNA。我们的系统在大鼠体内进行全身性 Plekho1 siRNA 递送，导致 siRNA 在成骨细胞中选择性富集，并随后耗尽 Plekho1。生物成像分析进一步表明，这种方法显著促进了骨形成，增强了骨微结构，并增加了健康和骨质疏松大鼠的骨量。这些结果表明（AspSerSer）（6）-脂质体是一种有前途的基于 RNA 干扰的骨合成治疗的靶向递送系统。
