TTR Platform

The amyloidoses are diseases induced by accumulation of various insoluble fibrillar proteins (amyloid) in the tissues in amounts sufficient to impair normal function. TTR is one of 20 proteins that are known to form fibrillar deposits in human amyloidoses.

TTR, a 127-amino acid, 55 kDa protein, primarily synthesized in the liver, is a secreted protein present in the blood and cerebrospinal fluid and is a carrier of thyroxine and retinol-binding protein-retinol (vitamin A) complex. In its native state, TTR exists as a homotetramer with two C2 symmetric funnel-shaped thyroxine binding sites located at the central dimer-dimer interface.

Both wild-type and mutated variants of TTR are involved in amyloid disease, but a mutation in TTR accelerates the process of TTR fibrillogenesis and is the most important risk factor for TTR amyloidosis. There are now more than 80 TTR single site variants that have been associated with TTR amyloidosis – the transthyretin-associated hereditary amyloidoses (ATTR). ATTR are the most prevalent type of hereditary systemic amyloidosis. TTR is deposited primarily in the peripheral nerves (ATTR-PN) and the heart (ATTR-CM), as well as in the gastrointestinal tract, vitreous (eye), and elsewhere.

The rate determining step for TTR amyloid formation is tetramer dissociation. All disease-associated mutations characterized thus far destabilize the TTR tetramer. Suppressors of disease-associated mutations have been reported and provide insight into the molecular mechanisms for disease treatment. The suppressors are intragenic, occur on the second TTR allele, and stabilize the tetramer against dissociation. Binding of ligands at the TTR thyroxine binding sites, such as thyroxine or non-steroidal anti-inflammatory drugs (NSAID), also stabilize the tetramer.. Thus, a small molecule stabilizer of tetrameric TTR is a potential disease-modifying therapy for TTR amyloidosis. This hypothesis forms the basis of the FoldRx development program for tafamidis  (Fx-1006A) in the treatment of TTR-associated amyloidosis.