Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition

Significance Transthyretin (TTR) cardiac amyloidosis is characterized by the deposition of TTR amyloid fibrils in the heart. No therapy is currently available for wild-type cardiac amyloidosis. Hereditary cases are treated by liver transplantation, a crude form of gene therapy which replaces amyloidogenic mutant TTR by the more stable wild-type form, with the goal of halting further deposition and disease progression. However, wild-type TTR continues to deposit in the heart of many patients after the procedure. Until now, seeding of TTR fibril formation has not been demonstrated in vitro. We show that patient-extracted cardiac fibrils can seed both wild-type and mutant TTR fibril formation in vitro. This process can be inhibited by structure-based peptide inhibitors, thereby providing an alternative approach to therapy. Each of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutant TTR gene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.