Hayashi Yuya, Jono Hirofumi
Department of Pharmacy, Kumamoto University Hospital.
Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University.
Biol Pharm Bull. 2018;41(12):1737-1744. doi: 10.1248/bpb.b18-00625.
Transthyretin (TTR) amyloidosis, also known as transthyretin-related familial amyloidotic polyneuropathy (ATTR-FAP), is a fatal hereditary systemic amyloidosis caused by mutant forms of TTR. Although conventional treatments for ATTR-FAP, such as liver transplantation (LT) and TTR tetramer stabilizer, reportedly halt the progression of clinical manifestation, these therapies have several limitations. Oligonucleotide-based therapy, e.g. small interfering RNA (siRNA)- and antisense oligonucleotides (ASOs)-based therapy, hold enormous potential for the treatment of intractable diseases such as ATTR-FAP, by specifically regulating the gene responsible for the disease. Clinical evidence strongly suggests that LT inhibits mutant TTR production, thus improving the manifestation of ATTR-FAP. Therefore, an oligonucleotide-based therapy for ATTR-FAP, which reduces the production of TTR by the liver, has recently been developed in preclinical and clinical studies. This review focuses on recent advances in oligonucleotide-based therapy and future prospects of next-generation oligonucleotide-based drugs for therapeutic use against ATTR-FAP.
转甲状腺素蛋白（TTR）淀粉样变性，也称为转甲状腺素蛋白相关家族性淀粉样多神经病（ATTR-FAP），是一种由TTR突变形式引起的致命遗传性全身性淀粉样变性。尽管据报道，针对ATTR-FAP的传统治疗方法，如肝移植（LT）和TTR四聚体稳定剂，可阻止临床表现的进展，但这些疗法存在一些局限性。基于寡核苷酸的疗法，例如基于小干扰RNA（siRNA）和反义寡核苷酸（ASO）的疗法，通过特异性调节致病基因，在治疗诸如ATTR-FAP等难治性疾病方面具有巨大潜力。临床证据有力地表明，肝移植可抑制突变型TTR的产生，从而改善ATTR-FAP的表现。因此，最近在临床前和临床研究中开发了一种基于寡核苷酸的ATTR-FAP疗法，该疗法可减少肝脏中TTR的产生。本综述重点关注基于寡核苷酸疗法的最新进展以及下一代用于治疗ATTR-FAP的寡核苷酸类药物的未来前景。
