Scripps Research Institute
Discovering a Drug to Ameliorate a Human Amyloid Disease at The Scripps Research Institute
The transthyretin amyloidoses are a group of degenerative diseases putatively caused by the misfolding and aggregation of transthyretin, a normal plasma protein. The Kelly lab has been studying the mechanism of the transthyretin aggregation for more than 20 years. This insight enabled them to produce the drug tafamidis that potently inhibits transthyretin aggregation by preventing transthyretin tetramer dissociation, which is rate-limiting for transthyretin aggregation. The non-native transthyretin aggregates both circulate and are deposited primarily in the autonomic and peripheral nervous system or the heart, and later in the disease course in the central nervous system. Using both pharmacology and by interpreting human genetic observations, the Kelly Lab demonstrated that preventing transthyretin aggregation arrests or slows degenerative disease progression in 2/3 of the patients. They provide compelling evidence that the process of transthyretin aggregation causes the degenerative phenotypes associated with the transthyretin amyloidoses–supporting the amyloid hypothesis of neurodegeneration.