Transthyretin (ATTR)
amyloidosis is a life-threatening, gain-of-toxic-function disease characterised by extracellular deposition of
amyloid fibrils composed of
transthyretin (TTR). TTR
protein destabilised by TTR gene mutation is prone to dissociate from its native tetramer to monomer, and to then misfold and aggregate into
amyloid fibrils, resulting in autosomal dominant
hereditary amyloidosis, including
familial amyloid polyneuropathy, familial
amyloid cardiomyopathy and familial leptomeningeal
amyloidosis. Analogous misfolding of wild-type TTR results in senile systemic
amyloidosis, now termed wild-type ATTR
amyloidosis, characterised by acquired
amyloid disease in the elderly. With the availability of genetic, biochemical and immunohistochemical diagnostic tests, patients with ATTR
amyloidosis have been found in many nations; however, misdiagnosis is still common and considerable time is required before correct diagnosis in many cases. The current standard first-line treatment for hereditary ATTR
amyloidosis is
liver transplantation, which allows suppression of the main source of variant TTR. However, large numbers of patients are not suitable transplant candidates. Recently, the clinical effects of TTR tetramer stabilisers,
diflunisal and
tafamidis, were demonstrated in randomised clinical trials, and
tafamidis has been approved for treatment of hereditary ATTR
amyloidosis in European countries and in Japan. Moreover,
antisense oligonucleotides and small interfering RNAs for suppression of variant and wild-type TTR synthesis are promising therapeutic approaches to ameliorate ATTR
amyloidosis and are currently in phase III clinical trials. These newly developed
therapies are expected to be effective for not only hereditary ATTR
amyloidosis but also wild-type ATTR
amyloidosis.