Jeffery W. Kelly

Jeffery W. Kelly, H. Lutcher Brown Professor of Chemistry at The Scripps Research Institute, received his Ph.D. in chemistry from the University of North Carolina (1986), followed by postdoctoral training at The Rockefeller University (1986–89). The central focus of the Kelly lab’s research is to understand the kinetic competition between protein folding, misfolding, and aggregation—the latter process being associated with neurodegenerative diseases. Knowledge gained from these investigations is used to develop new therapeutic strategies for diseases of protein conformation, including amyloid diseases.

The Kelly lab discovered the first drug to slow the progression of a human amyloid disease by inhibiting protein aggregation—tafamidis, Pfizer’s third best-selling medicine. He translated a genetic observation regarding transthyretin amyloidosis into a mechanistic biochemical understanding of amyloid disease prevention. Tafamidis inhibits transthyretin aggregation by binding to and kinetically stabilizing the native tetrameric transthyretin conformation, dramatically slowing tetramer dissociation, the rate-limiting step of transthyretin aggregation. Tafamidis was the first drug to demonstrate the importance of protein aggregation as a driver of human amyloid diseases.

The Kelly lab is currently pursuing the development of a light chain kinetic stabilizer in immunoglobulin light chain amyloidosis clinical trials, as well as the preclinical development of autophagy/lysosome pathway activators.

An author of more than 425 papers (ISI h-index = 110), Professor Kelly is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. He has mentored 47 trainees who have gone on to academic positions and over 70 trainees now working in the biotechnology and pharmaceutical industries.

The Work 

Jeffery W. Kelly’s insightful mechanistic studies on protein aggregation led to the discovery of tafamidis, the first effective drug for slowing the progression of a human amyloid disease, specifically transthyretin amyloidosis. Transthyretin amyloidosis occurs when the normally stable tetrameric protein, transthyretin, dissociates, misfolds and forms harmful clumps and fibers that damage nervous systems and organs. Disease-causing mutations, as well as aging-associated processes in the case of wild-type transthyretin weaken this tetramer leading to polyneuropathy / dementia and cardiomyopathy, respectively.  

Tafamifis binds to and stabilizes the tetramer, preventing it from breaking apart and forming damaging aggregates. Dr. Kelly’s laboratory also identified naturally occurring genetic variations, called interallelic trans-suppressor mutations, that slow tetramer dissociation, explaining why some individuals are protected from the disease. 

Tafamidis inhibits newly made transthyretin from aggregating and depositing in tissue, without clearing the amyloid fibrils already deposited, suggesting that the soluble aggregates in circulation play a critical role in neurodegeneration.

The Impact 

In the early 1990s, Kelly was among the first to demonstrate the foundational concept that protein shape changes alone were sufficient to convert proteins into aggregates, including amyloid fibrils. By translating these mechanistic insights into a pharmacological strategy to prevent these shape changes, he provided the first drug-based evidence that the healthspan and lifespan of patients afflicted with the third most common amyloid disease, transthyretin amyloidosis could be extended through inhibiting transthyretin aggregation. Seventy thousand patients are taking the Pfizer drug tafamidis for this purpose, discovered in Kelly’s laboratory.

Beyond transthyretin amyloidosis, this achievement shifted scientific and medical consensus toward embracing aggregation modulation as a viable therapeutic strategy, catalyzing the development of ten aggregation-modulating therapies that are now regulatory agency approved for treating human amyloid diseases, such as for ameliorating Alzheimer’s disease, hereditary ALS, and other protein-misfolding disorders. His discoveries established a new paradigm for treating neurodegenerative diseases, offering hope to millions and showing that controlling protein aggregation can fundamentally change the course of these devastating illnesses.