| Budget Amount *help |
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
Transthyretin (TTR) tetramer dissociation, misfolding and misassembly are required for the process of amyloid fibril formation associated with familial amyloid polyneurcpathy (FAP). Preferential stabilization of the native 'nit tetramer over the dissociative transition state by small molecule binding raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. First of all, we screened already approved drugs, and found that two NSAIDs, diflunisal and flufenamic add, stsbilize the native nu tetramer stracture and strongly inhibit TTR amyoidd fibril formation in vitro Next, we investigated the feasibility of using these molecules for the treatment of FAP utilizing serum samples from 37 FAP patients with 10 different mutations. We demonstrated that the TTR heterotetramer structures in FAP patients serum are significantly less stable than that in normal subjects, indicating the instability of the variant lilt structure is a fundamental cause of TTR amyloidosis. We also demonstrated that therapeutic serum concentrations of diflunisal stabilized serum variant TTR tetramer better than those of flufenamic acid. Importantly, diflunisal increased serum TTR. stability in FAP patients beyond the level of normal controls, indicating that diflunisal could be as effective as liver transplantation, which has proven to be an effective therapeutic strategy Based on these findings, we analyzed the effects of orally administered diflunisal on the serum Tilt tetramer stability in 15 FAP patients (phase II clinical trial). Orally administered diflunical significantly increased serum TM stability in FAP patients against add denaturation without side effects. To evaluate precise clinical effects of diflunisal, placebo-control double blind clinical trial is now enrolling patients internationally.
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