Recent advances in transthyretin amyloidosis therapy

Abstract

Mutant (MT) forms of transthyretin (TTR) cause the most common type of autosomal-dominant hereditary systemic amyloidosis—familial amyloidotic polyneuropathy (FAP). Until 20 years ago, FAP was thought to be an endemic disease, but FAP is known to occur worldwide. To date, more than 130 mutations in the TTR gene have been reported. Genotype-phenotype correlations are seen in FAP, and some variation in clinical presentation is often observed in individual kindreds with the same mutation and even among family members. Of the pathogenic TTR mutations, Val30Met was the first to be identified and is the most frequent known mutation found throughout the world. Studies of patients with FAP amyloidogenic TTR (ATTR) Val30Met documented sensorimotor polyneuropathy, autonomic dysfunction, heart and kidney failure, gastrointestinal tract (GI) disorders, and other symptoms leading to death, usually within 10 years of the onset of disease. Diagnosis is sometimes delayed, especially in patients without a clear family history and typical clinical manifestations, since diagnosis requires various studies and techniques such as histopathology, genetic testing, and mass spectrometry. For treatment of FAP, liver transplantation (LT) reportedly halts the progression of clinical manifestations. Exchange of an FAP patient’s diseased liver with a healthy liver causes MT TTR in the body to be replaced by wild-type (WT) TTR. Although clinical evaluations indicated that progression of other clinical symptoms such as peripheral neuropathy, GI symptoms, and renal involvement usually halted after LT in FAP ATTR Val30Met patients, recent studies suggested that LT failed to prevent progression of cardiac amyloidosis in FAP ATTR Val30Met patients after LT, with this failure reportedly being due to continued formation of amyloid that derived mainly from WT TTR secreted from the transplanted non-mutant liver graft. In recent years, many therapeutic strategies have been proposed, and several ongoing therapeutic trials involve, for example, stabilizers of TTR tetramers (tafamidis and diflunisal) and gene therapies to suppress TTR expression (antisense methods and use of small interfering RNAs). These novel therapies may prove to prevent progression of FAP.

Identification and Assessment of Cardiac Amyloidosis by Myocardial Strain Analysis of Cardiac Magnetic Resonance Imaging

“…Although FAP was thought to be restricted to an endemic presence in specific areas, especially Portugal, Sweden, and Japan, progress in biochemical and molecular genetic analyses has shown that it is present throughout the world and more than 130 mutations in the TTR gene have been reported. 4 The treatments are liver transplantation and new drugs (diflunisal and tafamidis) to stabilize TTR, 13 which are usually effective. The median survival exceeds 20 years; 14 the reported 5-year survival rate is 92%.…”

Inhibition of the Amyloidogenesis of Transthyretin by Natural Products and Synthetic Compounds

“…Tafamidis has been approved in Europe, Japan, Mexico, and Argentina, but only for the treatment of early-stage FAP. 2,36) However, tafamidis was unable to halt the progression of the disease in patients with advanced FAP caused by the V30M mutation. 37) Therefore, the development of other drugs is of great importance for the treatment of ATTR.…”

“…Clinical trials have been conducted to assess the efficacy of diflunisal on the progression of ATTR. 2,3,5) In addition, a new drug, tafamidis, has been developed for the treatment of FAP. Tafamidis binds with high affinity to the T4-binding pockets of the TTR tetramer, leading to stabilization of the tetramer and inhibition of the amyloidogenesis 35) (Fig.…”

“…2,3) Hereditary ATTR (FAP, FAC, and CNSA) is an autosomal dominant disease that is caused by mutations in the TTR gene. Almost all of the patients are heterozygotes, namely, their TTR tetramers are composed of mutant and/or wild-type subunits.…”

“…It can be seen in people as young as their late twenties, and the average life expectancy after the onset of symptoms is about 10 years. 2,4) The clinical features of ATTR include sensorimotor polyneuropathy, autonomic dysfunction, heart and kidney failure, gastrointestinal tract disorders, vitreous opacity, cerebral infarction, and dementia.…”