期刊
CURRENT PHARMACEUTICAL DESIGN
卷 14, 期 30, 页码 3219-3230出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161208786404155
关键词
Transthyretin (TTR); amyloidosis; familial amyloid polyneuropathy (FAP); familial amyloid cardiomyopathy (FAC); senile systemic amyloidosis (SSA); protein misfolding; native state kinetic stabilization; diflunisal
资金
- Scientific Research [20590695]
- Intractable Disease Division, the Ministry of Health and Welfare, Amyloidosis Research Committee in Japan
- Skaggs Institute of Chemical Biology, the Lita Annenberg Hazen Foundation
- National Institutes of Health [DK046335]
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK046335, R29DK046335, R37DK046335] Funding Source: NIH RePORTER
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.
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