TTR

About TTR

TTR on chromosome 18q12.1 encodes transthyretin, a protein made mainly by the liver that circulates as a tetramer and transports thyroxine and retinol binding protein, which gives the protein its name. Dissociation of the tetramer into monomers that misfold and aggregate into amyloid fibrils is the key step in transthyretin amyloidosis. More than 100 TTR variants cause hereditary transthyretin amyloidosis, a progressive disease with peripheral and autonomic neuropathy, cardiomyopathy, or both. Val30Met, also written V50M, is the classic variant causing familial amyloid polyneuropathy, with historical clusters in Portugal, Sweden, and Japan, while V122I, common among people of West African ancestry, mainly causes cardiomyopathy. Wild type transthyretin can also form amyloid with age, causing wild type transthyretin cardiomyopathy, mostly in older men, often preceded by carpal tunnel syndrome. Treatments include tetramer stabilizers such as tafamidis and acoramidis, and silencers that reduce liver production of TTR, including the small interfering RNAs patisiran and vutrisiran and the antisense oligonucleotides inotersen and eplontersen. Liver transplantation was used historically for hereditary disease. In 2021 an in vivo CRISPR therapy for transthyretin amyloidosis became the first reported systemically administered gene editing treatment in humans.