核酸药物的研究进展

Current progress and prospects of nucleic acid-based therapeutics

从基因组的双链DNA(ds DNA),到编码和非编码RNA(m RNA、lnc RNA和mi RNA等),只要与疾病发生相关,都可能作为基因治疗的靶标。这些靶标可被替换、修复、补充、抑制或消除,取决于所采取的具体基因治疗方法。基因编辑技术是将致病基因裁剪缝补为正常的基因,而化学合成的和体内表达的核酸药物则主要靶向致病性RNA。与此同时,转运核酸药物的方法也在大力研发中,包括病毒或质粒表达载体和各种聚合物材料。核酸药物的成药性、转运载体的安全性和效率是基因治疗方法面临的挑战性问题。本文简要综述近年来基因治疗药物,特别是反义核酸、核酶、脱氧核酶、小干扰RNA(si RNA)和微小RNA(mi RNA)等化学合成的核酸药物,以及化学修饰在提高核酸药物的效价、抗酶解稳定性和有效转运等关键技术方面的进展。随着对基因调控在疾病发生过程中认识的逐步深入和核酸药物优化技术的进步,核酸药物的研发步伐将会越来越快,期待包括si RNA药物在内的更多核酸药物在不久的将来应用于临床治疗。

From genomic double strand DNA（ds DNA）to coding and noncoding RNA,such as messenger RNA（m RNA）,long non-coding RNA（lnc RNA）,micro RNA（mi RNA）,the pathologically related motifs could be replaced,restored,supplemented,inhibited or deleted,depending on the kinds of genetic therapeutics. The gene-editing technologies（CRISPR/Cas9）are being developed to repair the abnormal genes by insertion or deletion or replacement of mutated sequences in genomic ds DNA. Chemically synthesized and in vivo expressed nucleic acid drugs（antisense,si RNA,anti-mi RNA,mi RNA analogues,ribozymes,deoxyribozymes,aptamers）have been explored to target the disease-related RNAs. At the same time,many efforts have been concentrated on the delivery approaches for the nucleic acid therapeutics,including retrovirus-and plasmid-based expression vehicles and various polymer materials. The pharmacological properties of nucleic acid drugs,and the safety and transfer efficiency of the delivery vehicles are the major challenges to be tackled. In this review the development of genetic therapeutics in recent years is introduced,with the emphasis on the synthetic nucleic acid drugs and the pivotal role of chemical modifications in the enhancement of efficiency,nuclease resistance,and delivery of these nucleic acid drugs. With a deeper insight into the roles of genetic modulation in the pathological events,and the advances in chemical modifications,more nucleic acid drugs are expected for practical use in therapies.