Jeffery Kelly and the investigation of protein-folding mechanics

Proteins are built from genetic instructions within the cell. As they are built, they fold into origami-like shapes that are key to their function. Mistakes in their folding, or their ability to maintain a fold, can create misshapen clumps called amyloid plaques, a hallmark of many severe diseases, including Alzheimer’s.

Jeffery Kelly, a professor at Scripps Research, has spent much of his career asking whether neurodegenerative disease could be stopped by preventing the clumping of these amyloid plaques. Through painstaking work, he designed molecules that stabilize proteins in their correct shapes, much like a stick jammed into the spokes of a wheel can stop it from turning. His research led to the FDA-approved drug tafamidis (Vyndaqel® and Vyndamax®), a treatment that slows the progression of familial amyloid polyneuropathy (a neurodegenerative disease) and familial and sporadic TTR cardiomyopathy (a condition that leads to heart failure).

“Through the fashioning of small molecule drugs that can stabilize proteins against abnormal protein aggregation, I think we learned two really important things,” Kelly says. “One is the process of protein aggregation really does drive neurodegeneration. The second is that treating these patients early is absolutely critical.”

To that end, Kelly is now teaming with other experts at Scripps Research on a strategy to aid early diagnosis and improve the body’s ability to clear toxic protein clumps.