Exploring Mechanisms of Inhibition of Amyloid Seeding of Transthyretin

Amyloid deposition of the hormone transporter transthyretin causes familial and sporadic amyloidoses. The current treatment for familial cases is gene-therapy by liver transplantation. However, this procedure is often insufficient to stop subsequent cardiac deposition. Our recent work has shown that preformed amyloid fibrils present in the heart by the time of surgery can template or seed further polymerization of native transthyretin. No drugs have been approved to stop or slow this seeding process; the only treatment option is heart transplantation. Here we explore two potential inhibitory mechanisms. Of clinical significance, we found that tetramer stabilization does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex-vivo fibrils efficiently inhibits amyloid seeding in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach to be further explored.