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Joel Gottesfeld

Dedicated to Research for People with the Devastating Disease Friedreichs Ataxia

Driven by a love of science, Dr. Joel Gottesfeld, a professor in the Scripps Research Department of Molecular Biology, spent several decades working on basic research of how genes are controlled in human cells. He then came to the realization that he could use this knowledge to control gene expression in an effort to stop the progress of a variety of human diseases.

Joel currently researches the development of new therapeutics for human diseases, including cancer and neurodegenerative diseases.

Three years ago, Joel was reviewing a paper on the neurodegenerative disease, Friedreich's ataxia, which described the unusual DNA structure that is adopted by the gene mutation responsible for the disease.

"The article basically said, 'Wouldn't it be neat if we could find a small molecule that could fix this?" said Joel. "I looked at this as both a challenge and a chance to make an impact."

Since that day, Joel's team has developed compounds that reactivate the gene responsible for Friedreich's ataxia, offering hope for an effective treatment for this devastating and often deadly condition.

About one of every 20,000 to 50,000 people in the United States has Friedreich's ataxia, yet few people know about it. It is caused by a genetic defect that prevents adequate production of the protein frataxin. In neuronal and muscle cells, frataxin is essential for proper functioning of mitochondria, the energy producers for cells. Low levels of the protein lead to degeneration of nerve tissue in the spinal cord and nerves controlling muscle movement in the arms and legs.

Specific symptoms, which typically first appear between the ages of five and 15, include trouble walking, reduced hand coordination, and slurred speech. The disease also typically leads to scoliosis, heart disease, and diabetes. Most Friedreich's ataxia sufferers are eventually confined to a wheelchair and die as early adults due to associated heart disease.

"I've met the parents of many children affected with the disease and some of the patients and it would be just a dream to be able to help them," said Joel. "The parents are so thankful for our research and discoveries - it inspires me to do more."

"Dr. Gottesfeld's work holds tremendous promise of real therapeutic benefit for Friedreich's ataxia patients," said Ron Bartek, president of Friedreich's Ataxia Research Alliance (FARA). "His recent discovery appears to be our only near-term prospect for significantly increasing transcription of the frataxin gene. FARA is pleased to have been able to support this important work."

The HDAC inhibitor molecule that Joel and his colleagues developed for Friedreich's ataxia has been licensed to the biotechnology firm, Repligen, and is currently in preclinical development.

Other Freidreich's ataxia treatments under development are largely aimed at better treating symptoms of the disease, rather than grappling with the root cause of low frataxin production. Additional compounds that increase expression of frataxin protein have been developed, but are likely too toxic for therapeutic use. Gene therapies or stem cell treatments may eventually be available to increase frataxin production, but such options are probably many years off.

"Our small molecules offer a therapeutic approach to pursue in the near term," said Joel. "I'm very optimistic."

The class of molecules that Joel developed for Friedreich's ataxia may also be useful in Huntington's disease, certain forms of muscular dystrophy, and spinal muscular atrophy -- the number one genetic killer of children under the age of two, an inherited disease that destroys the nerves controlling voluntary muscle movement, which affects crawling, walking, head and neck control, and even swallowing.

"Taken together, thousands of patients could benefit from this class of molecules," said Joel.

Joel and his colleagues also have created a small molecule that blocks the replication of a wide variety of cancer cells, including cells derived from leukemia, prostate, pancreatic, cervical, colon, and bone cancers.

"The compound prevented any future growth of tumors in mice without obvious toxicity," said Joel. "It looked like the compounds actually caused the existing tumors to stop growing."

"These results are extremely exciting and could eventually lead to a new class of therapeutic agents directed against a broad spectrum of diseases," said Peter Wright, of the Scripps Research Molecular Biology Department.

Joel has been with Scripps Research since 1978. He is most impressed by the collegial atmosphere here and the excellence of his colleagues.

Joel received his Ph.D. in Biochemistry from California Institute of Technology, his M.Sc. in Biochemistry from Oxford University, and his B.A. in Biochemistry from the University of California, Berkeley.

While serving as a postdoctoral student at Cambridge, Joel worked closely with the acclaimed Dr. Francis Crick, who discovered the structure of DNA in 1953. "It was intimidating at first, but I got to know him well," said Joel. "He fostered open and free scientific discussions and was an inspiration to me."

In his spare time, Joel serves as Associate Editor of the Journal of Biological Chemistry, one of the leading scientific journals. Prior to that, he was on the editorial board for a decade. "After my research on Friedreich's ataxia, it is one of my most important and fulfilling endeavors," said Joel.

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"I've met the parents of many children affected with the disease and some of the patients and it would be just a dream to be able to help them," says Professor Joel Gottesfeld.