From Lab Bench to Bedside

Dr. Kelly
The misfolding and misassembly of proteins appears to be the underlying cause of many chronic and late-onset neurodegenerative diseases, including Parkinson’s, Alzheimer’s, and Huntington’s. Scientists have identified the misfolding of transthyretin, the second most prominent blood protein, as a key factor in the cause of these diseases.

In 1997, Scripps Research’s Jeffery Kelly, Lita Annenberg Hazen Professor of Chemistry, designed and synthesized several compounds that stabilized transthyretin. Partnering with venture capitalist Chris Mirabelli, Kelly founded FoldRx Pharmaceuticals, which took one of the compounds founded at Scripps Research into clinical trials. As a “kinetic stabilizer,” the compound locks transthyretin into an active shape and makes it nearly impossible for the protein to change into one of its problematic forms. Having fared well in Phase I trials, the compound has now entered Phase II/III trials for use in treating familial amyloid polyneuropathy and possibly other diseases that share similar causation.

With the success of FoldRx under their belts, Kelly and Mirabelli are now embarking upon a new “big idea company” with an even broader scope for managing the production of proteins to maintain health. ProteoStasis Therapeutics Inc. is aimed at finding a single drug that can treat multiple diseases caused by protein misproduction.

“Controlling protein maintenance could be very useful in a spectrum of diseases,” Kelly explains. Quality control – ensuring that functional proteins get to the right place and that defective ones don’t build up and cause disorders like Alzheimer’s – will be a major focus of the company. ProteoStasis’s CEO, David Pendergast, explains, “No one, to our knowledge, is focusing on the entire proteostasis network, and the signaling pathways that control it.” Pendergast adds that they are zeroing in on 500 to 600 key proteins which are arranged in pathways “that control how the other 22,000 proteins in your body get produced.”

Following the traditional route of translational medicine, it was only after Kelly’s team at Scripps Research had discovered the promising compounds that they were able to garner Mirabelli’s venture capital funding for additional work in return for a first shot at licensing their discoveries.

It is the early research, however, that is critical to starting the process – and for which funding is more difficult to secure. Kelly explains that funding from visionaries like the Skaggs family, who founded the Skaggs Institute for Chemical Biology at Scripps Research, was crucial to enabling this type of work. “[Their funding] empowers us to do the painstaking cutting edge research required for the development of first-in-class drugs that ameliorate important medical conditions.”

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