A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction

Significance Treating the transthyretin (TTR) amyloidoses early maximizes clinical response. Soluble nonnative protein oligomers are cytotoxic in cultured cell lines, in primary cells, and in animal models. Here we report an immunoassay for quantifying nonnative, oligomeric TTR (NNTTR) levels in human V30M TTR polyneuropathy plasma ( n = 81). High NNTTR pretreatment levels are significant for predicting which patients are less likely to respond to tafamidis ( P = 0.0025). The extent of NNTTR decrease does not differ between the tafamidis responders and nonresponders, suggesting that very high pretreatment NNTTR levels could reflect pathogenic processes that might not be ameliorated by solely reducing the amount of amyloidogenic substrate. Liver transplantation, as well as tafamidis and patisiran treatment, all lower NNTTR levels substantially.