Sekijima Yoshiki, Kelly Jeffery W, Ikeda Shu-ichi
Department of Neurology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Curr Pharm Des. 2008;14(30):3219-30. doi: 10.2174/138161208786404155.
Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein that transports both thyroxine (T(4)) and the retinol-retinol binding protein complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer misfolding and misassembly of variant TTR results in familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central nervous system amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in elderly populations. With the availability of genetic and immunohistochemical diagnostic tests, patients with TTR amyloidosis have been found in many nations worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic disease as previously thought. The only effective treatment for the familial TTR amyloidoses is liver transplantation; however, this strategy has a number of limitations, including a shortage of donors, a requirement for surgery for both the recipient and living donor, and the high cost. Furthermore, a large number of patients are not good transplant candidates. Recent studies focused on the TTR gene and protein have provided insight into the pathogenesis of TTR amyloidosis and suggested new strategies for therapeutic intervention. TTR tetramer (native state) kinetic stabilization by small molecule binding, immune therapy, and gene therapy with small interfering RNAs, antisense oligonucleotides, and single-stranded oligonucleotides are promising strategies based on our understanding of the pathogenesis of TTR amyloidosis. Among these, native state kinetic stabilization by diflunisal and Fx-1006A, a novel therapeutic strategy against protein misfolding diseases, are currently in Phase II/III clinical trials.
转甲状腺素蛋白（TTR）是一种同四聚体血清和脑脊液蛋白，可转运甲状腺素（T4）和视黄醇-视黄醇结合蛋白复合物（全RBP）。变体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家族性淀粉样多神经病（FAP）、家族性淀粉样心肌病（FAC）或家族性中枢神经系统淀粉样变性。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），其特征是老年人群中的散发性淀粉样变性。随着基因和免疫组织化学诊断测试的出现，在世界许多国家都发现了患有TTR淀粉样变性的患者。最近的研究表明，TTR淀粉样变性并非如先前认为的那样是一种罕见的地方病。家族性TTR淀粉样变性的唯一有效治疗方法是肝移植；然而，这种策略有许多局限性，包括供体短缺、受体和活体供体都需要手术以及成本高昂。此外，大量患者不适合进行移植。最近对TTR基因和蛋白质的研究为TTR淀粉样变性的发病机制提供了见解，并提出了新的治疗干预策略。基于我们对TTR淀粉样变性发病机制的理解，通过小分子结合、免疫疗法以及使用小分子干扰RNA、反义寡核苷酸和单链寡核苷酸的基因疗法来实现TTR四聚体（天然状态）的动力学稳定是很有前景的策略。其中，双氟尼酸和Fx-1006A（一种针对蛋白质错误折叠疾病的新型治疗策略）实现天然状态的动力学稳定目前正处于II/III期临床试验阶段。
