Transthyretin (TTR) is a homotetrameric serum and cerebrospinal fluid protein 
that transports both thyroxine (T(4)) and the retinol-retinol binding protein 
complex (holoRBP). Rate-limiting tetramer dissociation and rapid monomer 
misfolding and misassembly of variant TTR results in familial amyloid 
polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), or familial central 
nervous system amyloidosis. Analogous misfolding of wild-type TTR results in 
senile systemic amyloidosis (SSA) characterized by sporadic amyloidosis in 
elderly populations. With the availability of genetic and immunohistochemical 
diagnostic tests, patients with TTR amyloidosis have been found in many nations 
worldwide. Recent studies indicate that TTR amyloidosis is not a rare endemic 
disease as previously thought. The only effective treatment for the familial TTR 
amyloidoses is liver transplantation; however, this strategy has a number of 
limitations, including a shortage of donors, a requirement for surgery for both 
the recipient and living donor, and the high cost. Furthermore, a large number 
of patients are not good transplant candidates. Recent studies focused on the 
TTR gene and protein have provided insight into the pathogenesis of TTR 
amyloidosis and suggested new strategies for therapeutic intervention. TTR 
tetramer (native state) kinetic stabilization by small molecule binding, immune 
therapy, and gene therapy with small interfering RNAs, antisense 
oligonucleotides, and single-stranded oligonucleotides are promising strategies 
based on our understanding of the pathogenesis of TTR amyloidosis. Among these, 
native state kinetic stabilization by diflunisal and Fx-1006A, a novel 
therapeutic strategy against protein misfolding diseases, are currently in Phase 
II/III clinical trials.