Blocking amyloidosis

Familial amyloidosis is a rare inherited condition characterised by the build-up of abnormal deposits of the protein transthyretin (TTR) in various organs. Nearly 100 mutations in the TTR gene are known to cause amyloidosis. Affected individuals show early and severe impairment of the autonomous nervous system and also visual deterioration.

TTR is a tetrameric protein encountered in the serum and cerebrospinal fluid, and acts as a carrier of the thyroid hormone thyroxine. Inappropriate folding of the TTR leads to formation of insoluble fibrils.

The current standard treatment of familial TTR amyloidosis is liver transplantation, while certain small compounds have also demonstrated a stabilising effect on TTR. The EU-funded FIBRILLATION consortium proposed a different approach to stop TTR aggregation through the protective binding of specific non-natural peptides to TTR monomers.

Scientists analysed different segments of TTR, and demonstrated their capacity to form amyloid fibres. Key to this process was a particular part of the protein known as beta-strand F, which gets exposed in the monomeric form of the protein and can lead to TTR aggregation.

Taking advantage of this information, the consortium developed TTR-specific inhibitors that adhere to the strands F and H when TTR is in monomeric form. These inhibitors proved to prevent abnormal folding and aggregation of TTR in vitro.

To test the potential of the approach as a valid treatment, scientists plan to administer the inhibitors in animal models of the disease. Although very preliminary, the FIBRILLATION strategy offers a promising alternative to existing treatments.