Transthyretin (TTR) amyloid fibrils and non-fibrillar aggregates (ATTR)

Transthyretin (TTR) is a 55 kDa homotetrameric protein synthesized primarily in the liver and the choroid plexus, functioning as a carrier for thyroxine (T4) and the retinol-binding protein (RBP)-vitamin A complex (UniProt P02766). In transthyretin amyloidosis (ATTR), the TTR tetramer dissociates into unstable monomers that misfold and assemble into insoluble amyloid fibrils and non-fibrillar aggregates (PubMed PMID: 31019283). These deposits accumulate in the extracellular space of various organs, most notably the heart and peripheral nerves, leading to restrictive cardiomyopathy and progressive polyneuropathy (StatPearls: Transthyretin Amyloidosis). Therapeutic strategies focus on three main areas: stabilizing the native tetramer to prevent dissociation (e.g., tafamidis), silencing the TTR gene to reduce protein production (e.g., patisiran, vutrisiran), or using monoclonal antibodies to target and clear existing amyloid deposits (e.g., NI006) (PubMed PMID: 34103470). Effective management of ATTR requires early diagnosis and monitoring of biomarkers like NT-proBNP and serum TTR levels to assess treatment response and disease progression.

Other names

Transthyretin aggregatesATTR fibrilsMisfolded transthyretinPrealbumin amyloidTTR amyloid deposits

Kinetic stabilization of the TTR tetramer to prevent dissociation, RNA-targeted silencing of TTR protein synthesis via siRNA or antisense oligonucleotides, and antibody-mediated clearance of misfolded TTR aggregates.