Familial amyloidotic polyneuropathy (FAP) is a lethal autosomal dominant disease mediated by misfolding of transthyretin, a transport protein produced by the liver. Less than 200,000 patients with FAP exist in the United States, qualifying FAP for Orphan Disease status. Replacing amyloidogenic transthyretin gene by liver transplantation is the only effective therapy at present. A tetramer in its native state, transthyretin is only amyloidogenic when dissociated to its monomeric form. Our data indicates that diflunisal, a commercially available non-steroidal anti-inflammatory agent, stabilizes transthyretin tetramers, preventing amyloid fibril formation by misfolded transthyretin monomers. Our phase I human study demonstrated that moderate doses of diflunisal stabilized transthyretin tetramers with no evident toxicities. To examine the effect of diflunisal on mutated transthyretin tetramer stability and FAP disease progression, we propose conducting an international, multi-center, randomized, placebo-controlled, double blind trial comparing diflunisal 250 mg taken orally twice daily to no drug treatment. In the proposed study we will:
Aim 1. Define the effect of diflunisal on FAP disease progression over 2 years. A. We will employ validated composite neurologic scales and echocardiographic measures of infiltrative cardiomyopathy to serially assess end-organ disease state in patients with FAP receiving diflunisal or placebo over 2 years, using a randomized, double blind, multi-center design. B. The tolerability of daily diflunisal in FAP patients will be determined by monthly renal, liver, and hematologic indices.
Aim 2. Examine transthyretin tetramer stability in FAP patients randomly assigned to the diflunisal and placebo groups. The stability of tetrameric transthyretin (TTR) in the sera of FAP patients randomized to diflunisal or placebo treatment will be evaluated by PAGE analysis followed by immunoblotting. poiuytrewq c Diflunisal drug levels will be determined to assess treatment compliance. We will correlate FAP disease progression with TTR stabilization.
