Hwang Jihye, Chang Chanil, Kim Ji Hyun, Oh Chang Taek, Lee Ha Neul, Lee Changki, Oh Donghoon, Lee Changjin, Kim Beomjoon, Hong Sun Woo, Lee Dong-Ki
OliX Pharmaceuticals, Inc., Seoul, Korea.
Department of Dermatology, Chung Ang University Medical Center, Seoul, Korea.
J Invest Dermatol. 2016 Nov;136(11):2305-2313. doi: 10.1016/j.jid.2016.06.626. Epub 2016 Jul 15.
Connective tissue growth factor (CTGF) is a multifunctional matricellular protein, playing a role as a central mediator in tissue remodeling and fibrosis. A number of reports have shown the pivotal roles of CTGF in the progression of fibrosis, suggesting CTGF as a promising therapeutic target for the treatment of fibrotic disorders including hypertrophic scars and keloids. In this study, we present the development of an interfering RNA molecule that efficiently inhibits the expression of CTGF via RNA interference mechanism both in vitro and in vivo. Chemical modifications were introduced to the asymmetric interfering RNA (asiRNA) backbone structure. The resulting RNA molecule, termed cell-penetrating asiRNA (cp-asiRNA), entered into cells and triggered RNA interference-mediated gene silencing without delivery vehicles. The gene-silencing activity of cp-asiRNA targeting CTGF (cp-asiCTGF) was examined both in vitro and in vivo. Furthermore, the administration of cp-asiCTGF in the rat skin excision wound model efficiently reduced the induction of CTGF and collagens during the wound-healing process. These results suggest that the cp-asiCTGF molecule could be developed into antifibrotic therapeutics such as antiscar drugs.
结缔组织生长因子（CTGF）是一种多功能基质细胞蛋白，在组织重塑和纤维化过程中作为核心介质发挥作用。许多报告显示CTGF在纤维化进展中起关键作用，这表明CTGF有望成为治疗包括增生性瘢痕和瘢痕疙瘩在内的纤维化疾病的治疗靶点。在本研究中，我们展示了一种干扰RNA分子的研发，该分子通过RNA干扰机制在体外和体内均能有效抑制CTGF的表达。对不对称干扰RNA（asiRNA）主链结构进行了化学修饰。所得的RNA分子，称为细胞穿透性asiRNA（cp-asiRNA），无需递送载体即可进入细胞并触发RNA干扰介导的基因沉默。在体外和体内均检测了靶向CTGF的cp-asiRNA（cp-asiCTGF）的基因沉默活性。此外，在大鼠皮肤切除伤口模型中给予cp-asiCTGF可有效减少伤口愈合过程中CTGF和胶原蛋白的诱导。这些结果表明，cp-asiCTGF分子可开发成为抗纤维化治疗药物，如抗瘢痕药物。
