Chapter 4 - From uncovering the mechanism of transthyretin aggregation to the drug tafamidis for ameliorating neurodegeneration and cardiomyopathy

Abstract

The aggregation of transthyretin (TTR), one of ≈50 proteins that are known to misfold and aggregate in humans, leads to neurodegeneration and/or degeneration of other postmitotic tissues like the heart, depending on the TTR sequence(s) aggregating. Based on a detailed investigation into the mechanism of TTR aggregation, we demonstrated that TTR tetramer dissociation is the rate-limiting step for the process of TTR aggregation, allowing us to conceive of the small molecule “kinetic stabilizer” strategy for ameliorating the TTR amyloidoses. Kinetic stabilizers bind selectively to the native TTR tetramer over the dissociative transition state, making tetramer dissociation much slower and effectively stopping newly synthesized TTR from aggregating. We view pharmacologic kinetic stabilization as a conservative therapeutic approach in that it stops the entire process of aggregation of newly synthesized TTR. Thus, success does not require knowledge of which specific aggregate structures cause degeneration, nor does success hinge on understanding the mechanism by which aggregation destroys postmitotic tissue. Through two positive tafamidis clinical trials, along with a positive diflunisal repurposing kinetic stabilizer trial, we generated data that strongly support the amyloid hypothesis, the notion that the process of TTR aggregation drives the degenerative phenotypes in polyneuropathy and cardiomyopathy. Together the tafamidis polyneuropathy clinical trial and the diflunisal polyneuropathy clinical trial paved the way for the TTR mRNA lowering trials, whose positive outcomes further support the amyloid hypothesis. We also summarize the compelling human genetic support for the amyloid hypothesis in the context of the TTR amyloidoses at the end of this chapter.