This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Familial amyloid polyneuropathy (FAP) is a deadly inherited disease caused by misfolding of a modified liver protein-transhyretin. One amino acid substitution disrupts the normal clustering of transthyretin, promoting release of individual proteins that fold abnormally forming indestructible sheets of protein called amyloid. Ultimately, amyloid deposits in vital organs, impairing function. Typically, FAP patients die 7-15 years after diagnosis. No medical treatment exists. Our data indicate that diflunisal, a commercially available non-steroidal anti-inflammatory agent, stabilizes transthyretin clusters, preventing release of individual transthyretin molecules and production of amyloid. To test the ability of diflunisal to prevent disease worsening, we propose treating FAP patients with either diflunisal or empty pills (placebo) for at least two years. Monitoring their nerve, heart and kidney functions. The study will involve physician-scientists with expertise in FAP located in Portugal, Sweden, Japan and the United States -- all places where large numbers of patients with FAP live.
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