Koike Haruki, Katsuno Masahisa
Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
Biomedicines. 2019 Feb 5;7(1):11. doi: 10.3390/biomedicines7010011.
Transthyretin (TTR) amyloidosis is caused by systemic deposition of wild-type or variant amyloidogenic TTR (ATTRwt and ATTRv, respectively). ATTRwt amyloidosis has traditionally been termed senile systemic amyloidosis, while ATTRv amyloidosis has been called familial amyloid polyneuropathy. Although ATTRwt amyloidosis has classically been regarded as one of the causes of cardiomyopathy occurring in the elderly population, recent developments in diagnostic techniques have significantly expanded the concept of this disease. For example, this disease is now considered an important cause of carpal tunnel syndrome in the elderly population. The phenotypes of ATTRv amyloidosis also vary depending on the mutation and age of onset. Peripheral neuropathy usually predominates in patients from the conventional endemic foci, while cardiomyopathy or oculoleptomeningeal involvement may also become major problems in other patients. Electron microscopic studies indicate that the direct impact of amyloid fibrils on surrounding tissues leads to organ damage, whereas accumulating evidence suggests that nonfibrillar TTR, such as oligomeric TTR, is toxic, inducing neurodegeneration. Microangiopathy has been suggested to act as an initial lesion, increasing the leakage of circulating TTR. Regarding treatments, the efficacy of liver transplantation has been established for ATTRv amyloidosis patients, particularly patients with early-onset amyloidosis. Recent phase III clinical trials have shown the efficacy of TTR stabilizers, such as tafamidis and diflunisal, for both ATTRwt and ATTRv amyloidosis patients. In addition, a short interfering RNA (siRNA), patisiran, and an antisense oligonucleotide (ASO), inotersen, have been shown to be effective for ATTRv amyloidosis patients. Given their ability to significantly reduce the production of both wild-type and variant TTR in the liver, these gene-silencing drugs seem to be the optimal therapeutic option for ATTR amyloidosis. Hence, the long-term efficacy and tolerability of novel therapies, particularly siRNA and ASO, must be determined to establish an appropriate treatment program.
转甲状腺素蛋白（TTR）淀粉样变性是由野生型或变异型淀粉样变性TTR（分别为ATTRwt和ATTRv）的系统性沉积引起的。ATTRwt淀粉样变性传统上被称为老年系统性淀粉样变性，而ATTRv淀粉样变性则被称为家族性淀粉样多神经病。尽管ATTRwt淀粉样变性传统上被认为是老年人群中心肌病的病因之一，但诊断技术的最新进展显著扩展了这种疾病的概念。例如，现在认为这种疾病是老年人群中腕管综合征的重要病因。ATTRv淀粉样变性的表型也因突变和发病年龄而异。在传统的地方性病灶患者中，周围神经病变通常占主导，而在其他患者中，心肌病或眼软脑膜受累也可能成为主要问题。电子显微镜研究表明，淀粉样纤维对周围组织的直接影响导致器官损伤，而越来越多的证据表明，非纤维状TTR，如寡聚TTR，具有毒性，并可诱导神经变性。有人提出微血管病作为初始病变，会增加循环TTR的渗漏。关于治疗，肝移植对ATTRv淀粉样变性患者，特别是早发性淀粉样变性患者的疗效已经得到证实。最近的III期临床试验表明，TTR稳定剂，如tafamidis和双氟尼酸，对ATTRwt和ATTRv淀粉样变性患者均有效。此外，短干扰RNA（siRNA）帕替拉韦和反义寡核苷酸（ASO）依诺特森已被证明对ATTRv淀粉样变性患者有效。鉴于它们能够显著降低肝脏中野生型和变异型TTR的产生，这些基因沉默药物似乎是ATTR淀粉样变性的最佳治疗选择。因此，必须确定新型疗法，特别是siRNA和ASO的长期疗效和耐受性，以建立合适的治疗方案。
