Recent advances in transthyretin amyloidosis therapy.
Recent advances in transthyretin amyloidosis therapy.
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DOI：
10.1186/2047-9158-3-19
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发表时间：
2014
影响因子：
12.6
通讯作者：
Ando Y
中科院分区：
文献类型：
--
作者：
Ueda M;Ando Y
转甲状腺素(TTR)的突变(MT)形式可引起最常见的常染色体显性遗传性系统性淀粉样变性-家族性淀粉样多发性神经病(FAP)。直到20年前，FAP还被认为是一种地方病，但FAP已知在全球范围内发生。到目前为止，已经报道了130多个TTR基因突变。在FAP中可以观察到基因-表型的相关性，在具有相同突变的个体家系中，甚至在家庭成员之间，临床表现经常会有一些变化。在致病的TTR突变中，Val30Met是第一个被发现的，也是在世界各地发现的最常见的已知突变。对FAP淀粉样变性TTRVal30Met患者的研究发现，通常在发病10年内，患者会出现感觉运动性多神经病、自主神经功能障碍、心肾衰竭、胃肠道(GI)障碍和其他导致死亡的症状。诊断有时会延误，特别是在没有明确家族史和典型临床表现的患者，因为诊断需要各种研究和技术，如组织病理学、基因测试和质谱仪。据报道，对于FAP的治疗，肝移植(LT)可以阻止临床症状的进展。FAP患者患病的肝脏与健康的肝脏交换会导致体内的MT TTR被野生型(WT)TTR所取代。尽管临床评估显示，FAP ATTRVal30Met患者接受肝移植后，其他临床症状，如周围神经病变、胃肠道症状和肾脏损害的进展通常会停止，但最近的研究表明，LT未能阻止FAP ATTRVal30Met患者接受肝移植后心脏淀粉样变性的进展，据报道，这种失败是由于淀粉样蛋白的持续形成，淀粉样蛋白主要来自移植的非突变肝移植产生的WT TTR。近年来，许多治疗策略被提出，一些正在进行的治疗试验涉及TTR四聚体的稳定剂(他法米松和二氟尼柳)和基因治疗以抑制TTR的表达(反义方法和使用小干扰RNA)。这些新的治疗方法可能被证明可以防止FAP的进展。
Mutant (MT) forms of transthyretin (TTR) cause the most common type of autosomal-dominant hereditary systemic amyloidosis—familial amyloidotic polyneuropathy (FAP). Until 20 years ago, FAP was thought to be an endemic disease, but FAP is known to occur worldwide. To date, more than 130 mutations in the TTR gene have been reported. Genotype-phenotype correlations are seen in FAP, and some variation in clinical presentation is often observed in individual kindreds with the same mutation and even among family members. Of the pathogenic TTR mutations, Val30Met was the first to be identified and is the most frequent known mutation found throughout the world. Studies of patients with FAP amyloidogenic TTR (ATTR) Val30Met documented sensorimotor polyneuropathy, autonomic dysfunction, heart and kidney failure, gastrointestinal tract (GI) disorders, and other symptoms leading to death, usually within 10 years of the onset of disease. Diagnosis is sometimes delayed, especially in patients without a clear family history and typical clinical manifestations, since diagnosis requires various studies and techniques such as histopathology, genetic testing, and mass spectrometry. For treatment of FAP, liver transplantation (LT) reportedly halts the progression of clinical manifestations. Exchange of an FAP patient’s diseased liver with a healthy liver causes MT TTR in the body to be replaced by wild-type (WT) TTR. Although clinical evaluations indicated that progression of other clinical symptoms such as peripheral neuropathy, GI symptoms, and renal involvement usually halted after LT in FAP ATTR Val30Met patients, recent studies suggested that LT failed to prevent progression of cardiac amyloidosis in FAP ATTR Val30Met patients after LT, with this failure reportedly being due to continued formation of amyloid that derived mainly from WT TTR secreted from the transplanted non-mutant liver graft. In recent years, many therapeutic strategies have been proposed, and several ongoing therapeutic trials involve, for example, stabilizers of TTR tetramers (tafamidis and diflunisal) and gene therapies to suppress TTR expression (antisense methods and use of small interfering RNAs). These novel therapies may prove to prevent progression of FAP.