Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL, USA.
J Neurochem. 2021 Mar;156(6):802-818. doi: 10.1111/jnc.15233. Epub 2020 Dec 3.
The liver-derived, circulating transport protein transthyretin (TTR) is the cause of systemic hereditary (ATTRv) and wild-type (ATTRwt) amyloidosis. TTR stabilization and knockdown are approved therapies to mitigate the otherwise lethal disease course. To date, the variety in phenotypic penetrance is not fully understood. This systematic review summarizes the current literature on TTR pathophysiology with its therapeutic implications. Tetramer dissociation is the rate-limiting step of amyloidogenesis. Besides destabilizing TTR mutations, other genetic (RBP4, APCS, AR, ATX2, C1q, C3) and external (extracellular matrix, Schwann cell interaction) factors influence the type of onset and organ tropism. The approved small molecule tafamidis stabilizes the tetramer and significantly decelerates the clinical course. By sequence-specific mRNA knockdown, the approved small interfering RNA (siRNA) patisiran and antisense oligonucleotide (ASO) inotersen both significantly reduce plasma TTR levels and improve neuropathy and quality of life compared to placebo. With enhanced hepatic targeting capabilities, GalNac-conjugated siRNA and ASOs have recently entered phase III clinical trials. Bivalent TTR stabilizers occupy both binding groves in vitro, but have not been tested in trials so far. Tolcapone is another stabilizer with the potential to cross the blood-brain barrier, but its half-life is short and liver failure a potential side effect. Amyloid-directed antibodies and substances like doxycycline aim at reducing the amyloid load, however, none of the yet developed antibodies has successfully passed clinical trials. ATTR-amyloidosis has become a model disease for pathophysiology-based treatment. Further understanding of disease mechanisms will help to overcome the remaining limitations, including application burden, side effects, and blood-brain barrier permeability.
肝脏来源的循环转运蛋白转甲状腺素蛋白（TTR）是系统性遗传性（ATTRv）和野生型（ATTRwt）淀粉样变性的原因。TTR 的稳定和敲低是减轻这种致命疾病进程的已批准治疗方法。迄今为止，表型外显率的多样性尚不完全清楚。本系统综述总结了 TTR 病理生理学及其治疗意义的当前文献。四聚体解离是淀粉样生成的限速步骤。除了不稳定的 TTR 突变外，其他遗传（RBP4、APCS、AR、ATX2、C1q、C3）和外部（细胞外基质、施万细胞相互作用）因素影响发病类型和器官嗜性。已批准的小分子塔法米迪稳定四聚体，并显著减缓临床病程。通过序列特异性 mRNA 敲低，已批准的小干扰 RNA（siRNA）帕替沙尼和反义寡核苷酸（ASO）依洛硫酸酯均显著降低血浆 TTR 水平，并与安慰剂相比改善神经病变和生活质量。具有增强的肝靶向能力，GalNac 缀合的 siRNA 和 ASO 最近已进入 III 期临床试验。双价 TTR 稳定剂在体外占据两个结合槽，但迄今为止尚未在试验中进行测试。托卡朋是另一种具有穿透血脑屏障潜力的稳定剂，但半衰期短，肝功能衰竭是潜在的副作用。针对淀粉样蛋白的抗体和多西环素等物质旨在减少淀粉样蛋白负荷，但迄今为止尚未成功开发出任何一种抗体通过临床试验。ATTR 淀粉样变性已成为基于病理生理学的治疗的模型疾病。进一步了解疾病机制将有助于克服尚存的局限性，包括应用负担、副作用和血脑屏障通透性。
