Transthyretin amyloid fibrils (ATTR) (ATTR)

Transthyretin (TTR) is a transport protein produced mainly in the liver that circulates as a stable homotetramer, carrying thyroxine and retinol (UniProt: P02766). Transthyretin amyloidosis (ATTR) is a progressive, fatal disease characterized by the dissociation of this tetramer into unstable monomers, which misfold and self-assemble into toxic oligomers and insoluble amyloid fibrils (PMID: 31235032). These non-native aggregates deposit in extracellular spaces of organs such as the heart and peripheral nerves, causing structural damage and organ failure (PMID: 30134145). Pharmacological management involves three primary strategies: kinetic stabilization of the TTR tetramer to prevent misfolding (e.g., Tafamidis), suppression of TTR synthesis using RNA interference or antisense oligonucleotides (e.g., Patisiran, Inotersen), and the development of monoclonal antibodies that selectively target and clear existing amyloid deposits (e.g., NI006) (PMID: 36516060, PMID: 30134148). Current research focuses on improving the specificity of these treatments to reduce systemic toxicity and enhance the removal of established fibrils from affected tissues. Monitoring of treatment efficacy often involves measuring serum TTR levels and cardiac biomarkers like NT-proBNP.

Other names

Misfolded transthyretinNon-native transthyretin aggregatesATTR amyloidPrealbumin amyloidTTR aggregates

Kinetic stabilization of the native tetramer to prevent dissociation, inhibition of protein synthesis via RNA interference or antisense oligonucleotides, and antibody-mediated clearance of misfolded aggregates and fibrils.