Transthyretin amyloid fibrils and associated microcalcifications (ATTR fibrils)

Transthyretin (TTR) amyloid fibrils are insoluble protein aggregates formed from the misfolding and dissociation of the TTR tetramer, a transport protein produced primarily in the liver (UniProt P02766). These fibrils deposit in various tissues, most notably the myocardium and peripheral nerves, leading to transthyretin amyloidosis (ATTR). In the heart, these deposits are frequently associated with microcalcifications, which serve as the basis for non-invasive diagnostic imaging using bone-seeking radiopharmaceuticals like Technetium-99m pyrophosphate (PubMed: 31513331). While traditional therapies focus on stabilizing the TTR tetramer or silencing its production, novel therapeutic strategies specifically target the fibrils for clearance. Monoclonal antibodies, such as NI006, are being developed to recognize neo-epitopes on the misfolded protein, promoting immune-mediated removal of existing deposits (PubMed: 36652318). Addressing the fibrils directly offers the potential to reverse organ damage rather than just slowing disease progression.

Other names

ATTR amyloidTransthyretin aggregatesTTR amyloid depositsSenile systemic amyloidosisFamilial amyloid polyneuropathy depositsFamilial amyloid cardiomyopathy deposits

Therapeutic strategies include kinetic stabilization of the TTR tetramer to prevent dissociation, silencing TTR gene expression to reduce protein supply, and using monoclonal antibodies to target and clear existing amyloid fibrils via immune-mediated phagocytosis (PubMed: 36652318). Diagnostic agents interact with associated microcalcifications to visualize the amyloid burden (PubMed: 31513331).