In transthyretin amyloid diseases that present primarily as a cardiomyopathy, doctors have been able to stave off heart failure with a liver and heart transplant; familial amyloid polyneuropathy patients receiving a liver transplant can benefit, since the liver is the primary source of mutant, disease-associated TTR. For the 90 percent of patients surviving transplantation, this surgical form of gene therapy slows familial amyloid polyneuropathy progression, but does not stop it as the wild type transthyretin protein can continue to form amyloid.
Left untreated, the TTR amyloidoses are relentlessly progressive and inevitably fatal, with a course of about a decade from initial symptoms to death.
The Search for Treatments
Kelly began searching for TTR-amyloidogenesis-inhibitors in the mid 1990s, and a few years later began to focus on a family of TTR-binding compounds, the so-called benzoxazoles, whose basic design would further be elaborated into tafamidis using a structure-based drug design paradigm. In 2003, Kelly co-founded a Cambridge, Massachusetts-based biotechnology startup, FoldRx Pharmaceuticals (now a fully owned subsidiary of Pfizer), to develop these compounds and optimize one of them into an orally available drug for the treatment of the TTR amyloidoses. The result was tafamidis meglumine, whose preclinical tests remained unpublished until now.
Kelly and his colleagues designed tafamidis to bind to the natural, functional TTR structure (mutant and wild type), in a way that prevents it from deviating from this natural, functional form into the amyloid state. TTR's natural, functional form is a "tetramer" made from four copies of the protein. Amyloidosis occurs when these tetramers come apart and the individual TTR proteins ("monomers") undergo shape changes enabling them to misassemble into dysfunctional amyloid aggregates. Incl
|Contact: Mika Ono|
Scripps Research Institute