National Institute of Pharmaceutical Education and Research (NIPER) - Ahmedabad, Palaj, (An Institute of National Importance), Opposite Air Force Station, Gandhinagar, 382355, Gujarat, India.
Sci Rep. 2019 Nov 5;9(1):16047. doi: 10.1038/s41598-019-52390-4.
Small interfering RNA (siRNA) are synthetic RNA duplex designed to specifically knockdown the abnormal gene to treat a disease at cellular and molecular levels. In spite of their high potency, specificity, and therapeutic potential, the full-fledged utility of siRNA is predominantly limited to in vitro set-up. Till date, Onpattro is the only USFDA approved siRNA therapeutics available in the clinic. The lack of a reliable in vivo siRNA delivery carrier remains a foremost obstacle towards the clinical translation of siRNA therapeutics. To address the obstacles associated with siRNA delivery, we tested a dendrimer-templated polymeric approach involving a USFDA approved carrier (albumin) for in vitro as well as in vivo delivery of siRNA. The developed approach is simple in application, enhances the serum stability, avoids in vivo RNase-degradation and mediates cytosolic delivery of siRNA following the endosomal escape process. The successful in vitro and in vivo delivery of siRNA, as well as targeted gene knockdown potential, was demonstrated by HDAC4 inhibition in vitro diabetic nephropathy (DN) podocyte model as well as in vivo DN C57BL/6 mice model. The developed approach has been tested using HDAC4 siRNA as a model therapeutics, while the application can also be extended to other gene therapeutics including micro RNA (miRNA), plasmids oligonucleotides, etc.
小干扰 RNA（siRNA）是一种人工合成的 RNA 双链体，旨在特异性地敲低异常基因，从而在细胞和分子水平上治疗疾病。尽管 siRNA 具有高效性、特异性和治疗潜力，但它的广泛应用主要局限于体外实验。迄今为止，Onpattro 是唯一一种获得美国食品药品监督管理局批准的临床应用 siRNA 治疗药物。缺乏可靠的体内 siRNA 递送载体仍然是 siRNA 治疗药物临床转化的首要障碍。为了解决与 siRNA 递送相关的障碍，我们测试了一种树状聚合物方法，该方法涉及一种美国食品药品监督管理局批准的载体（白蛋白），用于 siRNA 的体外和体内递送。所开发的方法应用简单，可增强血清稳定性，避免体内核糖核酸酶降解，并在通过内体逃逸过程后介导 siRNA 的细胞质递送。通过在体外糖尿病肾病（DN）足细胞模型以及体内 DN C57BL/6 小鼠模型中抑制 HDAC4，证明了 siRNA 的成功体外和体内递送以及靶向基因敲低潜力。该方法已使用 HDAC4 siRNA 作为模型治疗药物进行了测试，而该应用也可以扩展到其他基因治疗药物，包括 micro RNA（miRNA）、质粒寡核苷酸等。
