Transthyretin stabilizers

Transthyretin (TTR) is a type of protein made up of 127 amino acids. It is called a transport protein, because it carries both thyroxine (T4) and retinol-binding protein bound to retinol, which is how its name is derived: trans- (transport), thyr- (thyroxine), retin (retinol). Transthyretin is found in the serum and cerebrospinal fluid and circulates as a hometramer, which is a protein complex made up of four identical subunits which are associated but not covalently bound.

Destabilization of TTR can occur from either inherited mutations or just due to aging. One of the more common mutations affects 3.4% of persons of African-American descent, and studies have revealed 13 to 32% of men over the age of 75 with heart disease have evidence of destabilization of TTR at autopsy.

Destabilization of TTR causes the hometramer complex to break apart and form amyloid fibrils (unwanted insoluble fiber aggregates that are resistant to degradation) that deposit in tissues and organs. Amyloid fibrils have been associated with conditions such as heart disease, heart failure, type 2 diabetes, and, controversially, Alzheimer’s disease.

What are TTR stabilizers?

TTR stabilizers act within the hometramer to prevent destabilization of TTR and dissociation into amyloid fibrils, therefore preventing progression of TTR amyloidosis. Tafamidis, an analog of the nonsteroidal anti-inflammatory drug diflunisal without NSAID properties, was the first specific TTR stabilizer to be approved by the FDA (May 2019) for the treatment of cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis (ATTR-CM). TTR stabilizers are generally well tolerated with urinary tract infections, vaginal infections, diarrhea, and upper abdominal pain being the most commonly reported side effects.