Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
Ann Clin Transl Neurol. 2024 Sep;11(9):2426-2438. doi: 10.1002/acn3.52158. Epub 2024 Aug 2.
Hereditary transthyretin (TTR) amyloidosis (ATTRv) is frequently complicated by polyneuropathy (ATTRv-PN) and cardiomyopathy (ATTRv-CM). The long-term efficacy of diflunisal on both polyneuropathy and cardiomyopathy in ATTRv patients, especially those with non-V30M genotypes, has not been fully investigated and compared with that of tafamidis.
We compared the structural and biochemical characteristics of A97S-TTR complexed with tafamidis with those of diflunisal, and prospectively followed up and compared the progression of polyneuropathy and cardiomyopathy between ATTRv-PN patients taking diflunisal and those taking tafamidis.
Both diflunisal and tafamidis effectively bind to the two thyroxine-binding sites at the A97S-TTR dimer-dimer interface and equally and almost sufficiently reduce amyloid fibril formation. Thirty-five ATTRv-PN patients receiving diflunisal and 22 patients receiving tafamidis were enrolled. Compared with no treatment, diflunisal treatment significantly delayed the transition of FAP Stage 1 to 2 and Stage 2 to 3 and decreased the deterioration in parameters of the ulnar nerve conduction study (NCS). The progression of FAP stage or NCS parameters did not differ between patients treated with diflunisal and those treated with tafamidis. Both diflunisal and tafamidis treatments significantly decreased radiotracer uptake on Tc-PYP SPECT and stabilized cardiac wall thickness and blood pro-B-type natriuretic peptide levels. No significant adverse events occurred during diflunisal or tafamidis treatment.
The binding patterns of both tafamidis and diflunisal to A97S-TTR closely resembled those observed in the wild type. Diflunisal can effectively delay the progression of polyneuropathy and cardiomyopathy with similar efficacy to tafamidis and may become a cost-effective alternative treatment for late-onset ATTRv-PN.
遗传性转甲状腺素蛋白（TTR）淀粉样变（ATTRv）常并发多发性神经病（ATTRv-PN）和心肌病（ATTRv-CM）。非 V30M 基因型 ATTRv 患者中，双水杨酯对多发性神经病和心肌病的长期疗效尚未得到充分研究，且尚未与他法米汀进行比较。
我们比较了 A97S-TTR 与他法米汀复合物以及与双水杨酯复合物的结构和生化特征，并前瞻性随访比较了服用双水杨酯和他法米汀的 ATTRv-PN 患者的多发性神经病和心肌病进展情况。
双水杨酯和他法米汀均能有效结合 A97S-TTR 二聚体-二聚体界面的两个甲状腺素结合位点，并能同等且几乎完全减少淀粉样纤维形成。纳入 35 例接受双水杨酯治疗和 22 例接受他法米汀治疗的 ATTRv-PN 患者。与未治疗相比，双水杨酯治疗显著延迟了 FAP 1 期向 2 期和 2 期向 3 期的转变，并降低了尺神经传导研究（NCS）参数的恶化。双水杨酯治疗组和他法米汀治疗组患者的 FAP 分期或 NCS 参数进展无差异。双水杨酯和他法米汀治疗均显著降低 Tc-PYP SPECT 放射性示踪剂摄取，并稳定了心脏壁厚度和血液 pro-B 型利钠肽水平。双水杨酯或他法米汀治疗期间均未发生重大不良事件。
他法米汀和双水杨酯与 A97S-TTR 的结合模式与野生型非常相似。双水杨酯能有效延缓多发性神经病和心肌病的进展，疗效与他法米汀相当，可能成为迟发性 ATTRv-PN 的一种具有成本效益的替代治疗方法。
