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CFTR：cystic fibrosis transmembrane conductance regulator protein

mR-509-3p：表達CFTR的mRNA

miR-509-3p：一種可以調節(jié)mR-509-3p的miRNA

PNA：肽核酸

囊胞性纖維癥是一種常見的基因突變導致的疾病，每3000個高加索人中就有一個患有此病。這個疾病使由于基因突變導致cystic fibrosis transmembrane conductance regulator (CFTR) protein 的表達發(fā)生變化，比如蛋白結構發(fā)生改變或者表達量減少，致使細胞某些功能功能喪失或者減弱。有不止一種突變類型的突變，CFTR蛋白還保留部分功能，因此，通過提高CFTR蛋白的表達量可以治療Cystic Fibrosis。 研究表明，細胞中存在miRNA，會調節(jié)CFTR的mRNA（miR-509-3p ）的翻譯，導致CFTR蛋白表達量減少。因此，可以通過減少miR-509-3p 對mR-509-3p 的影響來提高CFTR的表達量。之前的研究是直接設計一條跟miR-509-3p互補的PNA，通過PNA可以競爭性的與miR-509-3p的結合，從而抑制miR-509-3p對mR-509-3p的抑制作用。但研究表明，雖然針對miRNA的 PNA可以減少miRNA對相應mRNA的影響，但是同時也會影響很多其它的mRNA。這是因為一條miRNA可以調節(jié)幾百甚至幾千種mRNA 。

鑒于此，我們設計了另外一種方法來減少miR-509-3p對mR-509-3p的調節(jié)作用。 設計與mR-509-3p 的3′UTR 互補的PNA。 PNA與3′UTR 結合后，位點被保護，miR-509-3p就不會對mR-509-3p 有調節(jié)作用，從而miR-509-3p對mR-509-3p的抑制作用就減弱，CFTR蛋白的表達量就會得到明顯提高，患者的癥狀得到緩解。

實驗結果： 設計的13bp 的PNA 能顯著的提高CFTR蛋白的表達量（增加70%）。PNA能與相應的mRNA位點牢固結合，形成heteroduplexes ，從而保護了mRNA，不會被miRNA識別并結合。

Molecules 2017, 22(7), 1144; doi:10.3390/molecules22071144

原文要點：

In this paper, we have proposed for the first time the use of PNAs as miRNA target protectors to increase the expression of CFTR in CF. The negatively charged PNAs 1 and 2, conveniently modified at their C-ends and fully complementary to the 3’UTR region of the CFTR mRNA recognized by the seed region of miR-509-3p, were synthesized and characterized. To demonstrate the sequence dependent activity of 1 and 2, two other PNAs , containing scrambled sequences of 1 and 2, respectively, were designed and synthesized. Spectroscopic data confirmed the ability of 1 and 2 to bind their complementary ODN target by forming stable PNA/ODN heteroduplexes. The structural features of 1/RNA and 2/RNA heteroduplexes were also determined through molecular dynamics simulations. The results indicated that the presence of the negatively charged tetra peptide at the C-end of 1 and 2 slightly affected the structural features of the resulting PNA/RNA heteroduplexes (with respect to the experimentally determined PNA/RNA heteroduplexes). Biological studies show that the PNA molecules are suitable to counteract the action of miR-509-3p (in this case) as miRNA target protectors. These data confirm, once again, that a mRNA-targeted approach of a gene to increase the expression of the protein could be a good therapeutic strategy (that, of course, could be also used in other monogenic diseases). Moreover, the PNAs, showing a high affinity towards nucleic acid targets and forming stable heteroduplex complexes, represent excellent candidates to be used for this approach. Furthermore, this type of approach has the advantage of being relatively mutation-independent. For this reason, it would be sufficient to increase the expression of a protein, even if mutated, to exceed the threshold of minimal activity needed to obtain an optimal clinical phenotype.