Transthyretin amyloid (ATTR)

Misfolded transthyretin aggregates and amyloid deposits represent the pathological state of the transthyretin (TTR) protein, which normally functions as a transporter for thyroxine and retinol-binding protein (Source: UniProt P02766). In transthyretin-mediated amyloidosis (ATTR), the native TTR tetramer becomes unstable and dissociates into monomers that misfold and assemble into insoluble amyloid fibrils (Source: NIH StatPearls). These fibrils deposit in the extracellular space of various tissues, particularly the myocardium and peripheral nerves, leading to progressive organ failure (Source: Mayo Clinic). The accumulation of these deposits causes restrictive cardiomyopathy and debilitating polyneuropathy, which are the hallmarks of both hereditary and wild-type ATTR (Source: PubMed). Therapeutic intervention focuses on three main strategies: stabilizing the TTR tetramer to prevent misfolding (e.g., tafamidis), suppressing TTR production at the genetic level (e.g., patisiran), and clearing existing amyloid deposits (Source: NEJM). Specifically, investigational monoclonal antibodies like NI006 and PRX004 are designed to recognize and bind to the misfolded aggregates, triggering immune-mediated clearance (Source: Nature Reviews Drug Discovery). This target is of high clinical interest as clearing existing deposits may offer the possibility of reversing disease progression rather than just slowing it (Source: ClinicalTrials.gov).

Other names

Misfolded transthyretinTTR amyloid depositsTransthyretin aggregatesATTR fibrilsAmyloid transthyretinMisfolded TTR

Kinetic stabilization of the transthyretin tetramer to prevent dissociation, suppression of transthyretin synthesis via RNA interference or antisense oligonucleotides, and monoclonal antibody-mediated clearance of existing amyloid deposits.