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Jeff Kelly

Homing in on New Drugs to Fight Neurodegenerative Diseases

Top-notch researcher Jeff Kelly, chair of Scripps Research’s Department of Molecular and Experimental Medicine and the Lita Annenberg Hazen Professor of Chemistry, is working toward a cure for Alzheimer’s, Parkinson’s, and other neurodegenerative diseases. And he is determined to get there.

Jeff’s work employs a multidisciplinary approach to understand the biology and chemistry of the misfolding and misassembly of proteins, which appears to be the underlying cause of many chronic and late-onset neurodegenerative diseases, including well-known conditions such as Alzheimer’s and Parkinson’s, as well as rarer diseases, such as Huntington’s, familial amyloid neuropathy, familial amyloid cardiomyopathy, and inclusion body mitosis. Jeff is one of the world’s leading experts in protein misfolding diseases and his goal is to develop novel therapeutic strategies to fight them.

In 1997, Jeff and his colleague Evan Powers designed and synthesized several compounds that stabilized transthyretin, a protein found in blood. Transthyretin is the second most prominent blood protein and can be found in all of us. Unfortunately, in some people this protein misfolds and misassembles into a structured aggregate referred to as amyloid fibrils and this process, known as amyloidogenesis, can cause a variety of diseases The molecules discovered in Jeff’s lab prevented this process of amyloidogenesis.

These discoveries resulted in Vyndaqel® (tafamadis), which was recently approved by the European Medicines Agency for the treatment of familial amyloid polyneuropathy associated with transthyretin aggregation (TTR-FAP).

The initial symptoms of this inherited and ultimately fatal disease include loss of sensation, muscle weakness, and autonomic nerve dysfunction (including sexual dysfunction, gastrointestinal disorders and urinary problems) progressing to cardiac failure and loss of the ability to walk. The only previously known treatment available has been liver transplantation.

The European Commission approved Vyndaqel® to treat TTR-FAP in adult patients with stage 1 symptomatic polyneuropathy. The drug’s clinical studies demonstrated it significantly halted disease progression and reduced the burden of disease after 18 months, compared to placebo. Since transthyretin tetramer dissociation and monomer misfolding and aggregation (prevented by tafamidis) also causes cardiomyopathies, affecting hundreds of thousands of patients, there is reason to be optimistic that tafamidis will be useful for ameliorating senile systemic amyloidosis associated with wild type transthyretin aggregation (leads to congestive heart failure) and familial amyloid cardiomyopathy associated with mutant transthyretin amyloid fibril formation.

Tafamidis was developed by the company FoldRx Pharmaceuticals, cofounded by Jeff, and acquired by Pfizer in 2010.

Jeff beams about the role private philanthropy has played in his work.

“We’re so appreciative of our philanthropic funding that empowers us to do the painstaking, cutting-edge research required for development of first-in-class drugs,” said Jeff. “Because of philanthropy, we have been able to help and hope to continue to help people with disabling medical conditions that currently have no treatments.”

“I’m very excited tafamidis helps patients suffering from TTR amyloid diseases,” Jeff continued “Its development was built on years of basic scientific research, and we were fortunate to be funded by the Skaggs family, as well as the Lita Annenberg Hazen Foundation.”

The Skaggs family gave an extraordinarily generous gift of $100 million in 1996 which has helped transform Scripps Research into one of the leading biomedical research centers in the world.

The Arlene & Arnold Goldstein Family Foundation also provided a major gift to Jeff and his colleagues to develop the next generation of drugs to treat transthyretin amyloidosis.

“This category of human maladies represents a large unmet medical need and we appreciate the Goldsteins’ commitment to provide us with the resources to develop new therapeutic strategies for these degenerative disorders.”

A patient affected by amyloidosis, Goldstein was a participant in an ongoing FoldRx clinical trial.

The support of the Bruce and Anne Bundy Foundation has also been integral to Jeff’s work.

Jeff’s laboratory also worked on the drug, Diflunisal, which is currently being evaluated for the treatment of transthyretin associated neuropathy by an academic group of clinical investigators.

“Philanthropy to our lab has been transformative,” Jeff said. “The National Institutes of Health is becoming less of a partner and the future will require more and more philanthropy for us to operate.”

While Jeff and his colleagues have developed drugs for specific diseases, his next goal is to develop a drug that would treat multiple diseases at once.

And he plans to do this as part of a team. “I’m excited by the discoveries that the graduate students and postdoctoral fellows in our laboratory have made and will continue to make,” said Jeff.

A graduate of State University of New York at Fredonia, where he first got excited about science, Jeff received his Ph.D. from the University of North Carolina. He was a professor of chemistry at Texas A & M University before coming to Scripps Research, and, before that, a researcher at The Rockefeller University.

Jeff was recruited by former Scripps Research President Richard Lerner to come to the La Jolla campus in 1997. “It was a very easy decision,” said Jeff. “Scripps Research was emerging as the place to do chemical biology … plus La Jolla is a pretty nice place to live.”

Jeff also served as dean of graduate and postgraduate studies and dean and vice-president of academic affairs for many years, where he was responsible for Scripps Research’s Kellogg School of Science and Technology.  The school has been consistently recognized by U.S. News and World Report as among the top graduate programs in chemistry and biology in the nation.

Jeff is himself a philanthropist and has made Scripps Research the beneficiary designation of his retirement plan. “Scripps Research has been very good to me,” said Jeff. “I have no dependents and this is my way of giving something back in a way that will benefit society. Scripps Research needs philanthropic support for innovations in science and is one of the best charities around. I can’t think of a better gift than improving the quality of life for humankind and pushing forward the frontiers of science.”

Outside work, Jeff enjoys driving vintage race cars. Yet he says he takes far greater chances in the lab than he ever does on the track. The Scripps Research environment has allowed him to think big and tackle groundbreaking experiments.

“We have a unique environment here, because we don’t have departmental boundaries like many other universities,” said Jeff. “I have exceptional faculty, graduate student, and postdoctoral fellow colleagues and the freedom to spend a good fraction of the day thinking about and performing research – that’s becoming more and more difficult at universities.”

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“Because of philanthropy, we have been able to help and hope to continue to help people with disabling medical conditions that currently have no treatments,” says Kelly, chair of the Department of Molecular and Experimental Medicine, the Lita Annenberg Hazen Professor of Chemistry, and member of the Skaggs Institute for Chemical Biology at The Scripps Research Institute.