A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application
A chemically unmodified agonistic DNA with growth factor functionality for in vivo therapeutic application
复制标题
DOI：
10.1126/sciadv.aay2801
复制
发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Sando, Shinsuke
中科院分区：
文献类型：
--
作者：
Ueki, Ryosuke;Uchida, Satoshi;Sando, Shinsuke
虽然生长因子由于其再生功能而具有巨大的治疗潜力，但它们通常具有固有的缺点，例如热稳定性低和生产成本高。寡核苷酸最近已成为设计生长因子的合成替代品的有前途的化学实体。然而，由于它们对核酸酶的敏感性和对靶组织的有限分布，它们在体内的应用已被认为是一个挑战。在这里，我们提出了第一个例子，阿曲库肽为基础的生长因子模拟物，发挥治疗作用后，在靶组织全身注射。该适体被设计为使生长因子受体二聚化以使其活化并减轻小鼠模型中Fas诱导的暴发性肝炎的进展。适体的这种前所未有的功能可以通过其高核酸酶稳定性和向肝实质的迁移来合理地解释。这些机理分析为基于适体的受体激动剂的成功应用提供了见解。
Although growth factors have great therapeutic potential because of their regenerative functions, they often have intrinsic drawbacks, such as low thermal stability and high production cost. Oligonucleotides have recently emerged as promising chemical entities for designing synthetic alternatives to growth factors. However, their applications in vivo have been recognized as a challenge because of their susceptibility to nucleases and limited distribution to a target tissue. Here, we present the first example of oligonucleotide-based growth factor mimetics that exerts therapeutic effects at a target tissue after systemic injection. The aptamer was designed to dimerize a growth factor receptor for its activation and mitigated the progression of Fas-induced fulminant hepatitis in a mouse model. This unprecedented functionality of the aptamer can be reasonably explained by its high nuclease stability and migration to the liver parenchyma. These mechanistic analyses provided insights for the successful application of aptamer-based receptor agonists.