First Disease-Modifying Compound Targeting Protein Misfolding


transthyretin crystal structureThe term amyloidosis encompasses a wide variety of diseases characterised by extracellular deposition of insoluble fibrils of abnormally folded proteins in organs and tissues. Transthyretin amyloidosis (ATTR) is a disorder in which a serum protein, transthyretin (TTR), accumulates in tissues such as heart, kidneys, nerves, and intestine. TTR is a 127 amino acid transport protein for thyroxine and retinol which circulates as a tetramer. It is believed that the disease is caused by TTR tetramer dissociation into monomers which misfold and form amyloid deposits. The inherited form of the disease is caused by autosomal dominant mutations in the TTR gene. The only specific treatment at present for this progressive disorder is liver transplantation. TTR is synthesised primarily in the liver and, if an individual receives a new liver, they will no longer produce the mutated version of the protein. Although the procedure has benefitted some patients, for others disease progression continues after the transplant, suggesting that abnormal amyloid deposits may act as seeds, even for normal protein.

Scientists at the Scripps Research Institute investigating new treatments for ATTR have focussed on inhibition of tetramer dissociation, the rate-tafamidis structurelimiting step in amyloid formation, and discovered tafamidis (Fx-1006A), a small molecule that acts as a pharmacological chaperone for TTR and prevents misfolding. The drug stabilizes both wild-type and variant TTR, prevents misfolding of the protein by preventing tetramer dissociation, and inhibits the formation of TTR amyloid fibrils. Tafamidis is being developed by FoldRx Pharmaceuticals who announced last week that the new drug significantly halts disease progression for patients with transthyretin amyloid polyneuropathy (ATTR-PN), a form of ATTR in which the amyloid fibrils are deposited in peripheral nerve tissues. Results from a randomised, controlled Phase II/III clinical study showed that once daily oral treatment with tafamidis was safe and well-tolerated and, compared to placebo, significantly halted disease progression after 18 months (no progression in 60% of tafamidis patients compared with 38% of placebo patients). Placebo-treated patients also experienced a significant deterioration in quality of life compared with tafamidis-treated patients.

Tafamidis is the first disease-modifying compound that targets protein misfolding and it is hoped that it will provide a better alternative to liver transplant for ATTR-PN patients.

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