Abstract 1015 Structure-specific peptide probes detect aggregated transthyretin in plasma of transthyretin amyloidosis patients

The aggregation of the circulatory protein transthyretin leads to transthyretin amyloidosis (ATTR amyloidosis), an incurable condition that can lead to neuropathy and heart failure. We understand very little regarding the aggregation of transthyretin in ATTR amyloidosis, and this problem is exacerbated by a lack of tools that can be used to distinguish native transthyretin from amyloidogenic transthyretin (ATTR). Here we describe the development and evaluation of a peptide probe that targets aggregation-driving segments of transthyretin exposed only in its amyloidogenic state. We assessed the probe's activity and characterized its mechanism of binding to ATTR species using immunoblotting and electron microscopy. Our probe binds purified ATTR fibrils and ATTR species in cardiac tissue homogenates. Our probe also reveals the presence of previously unknown high molecular weight ATTR aggregates in the blood of cardiac ATTR amyloidosis patients. Using our probe, we find the presence of these aggregates in asymptomatic individuals carrying disease-triggering mutations, suggesting that they can precede tissue deposition and clinical manifestations. These aggregates are not found in healthy controls or other systemic amyloidosis patients and are reduced after treatment with disease-modifying interventions. Our study reveals a novel biomarker for ATTR amyloidosis and opens many questions regarding the aggregation of transthyretin in the blood and the pathophysiology of ATTR amyloidosis. This work was supported by the American Heart Association Career Development Award (847236) received by L.S., the NIH Director's New Innovator Award (DP2-HL163810-01) received by L.S., the NIH R01 (R01-HL160892) received by J.G., and the NIH grant 1S10OD021685-01A1 received by the Electron Microscopy Core of UTSW.