Sekijima Y
Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
J Clin Pharm Ther. 2014 Jun;39(3):225-33. doi: 10.1111/jcpt.12145.
Transthyretin (TTR) is a representative amyloidogenic protein in humans. Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR result in autosomal dominant familial amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) presenting as sporadic amyloid disease in the elderly. The objective of this review is to summarize recent progress in our understanding and treatment of TTR amyloidosis.
Literature searches were conducted on the topics of transthyretin, familial amyloid polyneuropathy and clinical trials, using PubMed, the United States clinical trials directory, pharmaceutical company websites and news reports. The information was collected, evaluated for relevance and quality, critically assessed and summarized.
The current standard first-line treatment of familial TTR amyloidosis is liver transplantation. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilizers, tafamidis and diflunisal, were demonstrated in randomized clinical trials, and tafamidis has been approved for the treatment of FAP in European countries and Japan. In addition, gene therapies with antisense oligonucleotides and small interfering RNAs are promising strategies to ameliorate TTR amyloidoses and are currently in clinical trials.
Liver transplantation to treat the familial TTR amyloidosis will likely be replaced by other less invasive therapies, such as TTR tetramer stabilizers and possibly gene therapy approaches. These newly developed therapies are expected to be effective for not only familial TTR amyloidosis but also SSA, based on their mechanisms of action.
转甲状腺素蛋白（TTR）是人体内一种典型的淀粉样蛋白生成蛋白。变异型TTR的限速四聚体解离以及快速的单体错误折叠和错误组装会导致常染色体显性遗传性家族性淀粉样变性。野生型TTR的类似错误折叠会导致老年系统性淀粉样变性（SSA），在老年人中表现为散发性淀粉样疾病。本综述的目的是总结我们在TTR淀粉样变性的认识和治疗方面的最新进展。
使用PubMed、美国临床试验目录、制药公司网站和新闻报道，对转甲状腺素蛋白、家族性淀粉样多神经病和临床试验等主题进行文献检索。收集信息，评估其相关性和质量，进行严格评估并总结。
家族性TTR淀粉样变性目前的标准一线治疗方法是肝移植。然而，大量患者不适合作为移植候选者。最近，TTR四聚体稳定剂tafamidis和双氯芬酸在随机临床试验中显示出临床效果，并且tafamidis已在欧洲国家和日本被批准用于治疗家族性淀粉样多神经病（FAP）。此外，使用反义寡核苷酸和小干扰RNA的基因疗法是改善TTR淀粉样变性的有前景的策略，目前正处于临床试验阶段。
治疗家族性TTR淀粉样变性的肝移植可能会被其他侵入性较小的疗法所取代，如TTR四聚体稳定剂以及可能的基因治疗方法。基于其作用机制，这些新开发的疗法预计不仅对家族性TTR淀粉样变性有效，对老年系统性淀粉样变性也有效。
