Transthyretin (TTR) amyloid aggregates (ATTR)

Transthyretin (TTR) amyloid aggregates are insoluble protein fibrils that result from the destabilization, dissociation, and misfolding of the native transthyretin tetramer (UniProt P02766). TTR is a transport protein synthesized primarily in the liver and the choroid plexus, responsible for carrying thyroxine and retinol-binding protein in the blood and cerebrospinal fluid (Hou et al., 2007). In transthyretin amyloidosis (ATTR), the misfolded monomers self-assemble into amyloid fibrils that deposit in the extracellular space of various tissues, most critically the heart and peripheral nerves, leading to progressive organ dysfunction (Gertz et al., 2015). Therapeutic strategies include kinetic stabilizers like tafamidis that bind the TTR tetramer to prevent its breakdown (Maurer et al., 2018), and genetic silencers like patisiran or inotersen that inhibit the production of the TTR protein at the mRNA level (Adams et al., 2018). More recently, investigational monoclonal antibodies such as NI006 have been developed to specifically target and clear existing misfolded aggregates from tissues by inducing phagocytosis (Garcia-Pavia et al., 2023).

Other names

ATTR amyloidTTR amyloid fibrilsMisfolded transthyretinAmyloid transthyretinTransthyretin deposits

Kinetic stabilization of the transthyretin tetramer to prevent dissociation; RNA interference (RNAi) or antisense oligonucleotide (ASO) mediated silencing of TTR mRNA to reduce protein production; Monoclonal antibody-mediated binding and clearance of misfolded aggregates.