Transthyretin amyloid deposits (ATTR)

Transthyretin (TTR) amyloid deposits are insoluble, pathological protein aggregates formed by the misfolding and subsequent assembly of transthyretin monomers into cross-beta sheet fibrils. In its healthy state, TTR is a tetrameric protein produced primarily in the liver that functions as a carrier for thyroxine and retinol-binding protein (UniProt: P02766). However, due to aging (wild-type ATTR) or genetic mutations (hereditary ATTR), the tetramer can become unstable and dissociate, leading to the accumulation of amyloid in the heart, nerves, and other organs, which causes progressive organ dysfunction (StatPearls: Transthyretin Amyloidosis). Pharmacological intervention focuses on three main pillars: stabilizing the TTR tetramer (e.g., Tafamidis), suppressing TTR synthesis at the genetic level (e.g., Patisiran, Inotersen), or utilizing investigational monoclonal antibodies to actively remove existing tissue deposits (NEJM: Tafamidis in Transthyretin Amyloid Cardiomyopathy).

Other names

Transthyretin amyloid fibrilsATTR fibrilsTTR amyloidAmyloid transthyretinMisfolded transthyretin

Therapeutic strategies include kinetic stabilization of the native transthyretin tetramer to prevent dissociation into amyloidogenic monomers, RNA interference (RNAi) or antisense oligonucleotide (ASO) mediated silencing of TTR mRNA to reduce protein production, and monoclonal antibodies designed to bind and clear existing amyloid deposits via phagocytosis.