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U of Minnesota, Celladon Researchers Collaborate on HT Assay for Heart Failure Rxs

NEW YORK (GenomeWeb News) – Researchers from the University of Minnesota and biotech firm Celladon have developed a high-throughput screening method that may help speed the development of drugs to treat heart failure, the university said this week.

Celladon, based in La Jolla, Calif., recently licensed exclusive rights to the technology from UM, and continues to work with researchers at the university to explore how the assay might be applied to other diseases, and to possibly conduct a large-scale screening campaign for drug candidates, officials said this week.

The method, developed by UM's David Thomas and Razvan Cornea, and Celladon's Krisztina Zsebo, uses a fluorescence sensing technique called fluorescence resonance energy transfer, or FRET, to screen for small molecules that can disrupt the interaction between a key regulatory protein called phospholamban and calcium pumps in cardiac cells, thereby promoting relaxation of the heart muscle.

"The target is the heart's calcium pump, which is regulated by phospholamban," Thomas, a professor of structural biology and biophysics at UM, told GenomeWeb Daily News this week.

"The idea is that phospholamban inhibits the pump, and that inhibition is relieved when phospholamban gets phosphorylated," Thomas said. "But the problem in heart failure is that the pump is not working enough, so inhibiting phospholamban is considered a bad thing when you have a failing heart. The idea is to somehow stop phospholamban from inhibiting the pump so much to allow the heart to recover and relax better."

Thomas said that drug companies have been trying to therapeutically target this regulatory pathway for the better part of a decade, and likewise have been trying to develop a reliable assay to screen for therapeutic candidates.

"The problem is they didn't have a really good assay for that – just an enzyme assay to measure the activity of the pump that was somewhat tedious – so it was hard to screen thousands of compounds," Thomas said.

Meantime, Thomas and colleagues at UM were conducting basic research using FRET – a technique that measures the interaction of two fluorescently labeled molecules by sensing changes in fluorescence emission – to directly measure the interactions of the proteins.

Specifically, they developed a way to conduct the FRET assay in a reconstituted membrane system composed of purified and synthesized lipid and protein components, a finding that they published in 2004 and that garnered the attention of Celladon, which is developing therapeutics to treat heart failure by targeting how calcium pumps regulate muscle contractility.

Celladon contacted Thomas' group that year and decided to sponsor research in the lab with Thomas as principal investigator to develop a high-throughput version of the assay for drug-discovery purposes. The research also eventually involved a large-scale screen of some 20,000 compounds as proof of principle and to generate some initial therapeutic hits, Thomas said.

According to John Merritt, director of communications in UM's Office of the Vice President for Research, Celladon provided approximately $230,000 in funding to further develop and test the assay, and inked an exclusive license for the technology with UM a few months ago.

The license gives Celladon the right to use the method in pharmaceutical product development, screening, and testing in humans and animals, as well as sub-licensing rights, Merritt said. Financial terms of the license agreement have not been disclosed. UM has also applied for a patent covering the technique and its applications.

Small-molecule therapies for heart failure constitute a new area for Celladon, an early 2000s spinout of the Mt. Sinai School of Medicine in New York. To this point, the company has focused primarily on developing gene therapies for heart failure that target deficiencies of the enzyme SERCA2a, which regulates calcium cycling and contractility in heart muscle cells.

As such, the company continues its sponsored research relationship with UM, and may eventually tap Thomas' lab to conduct another small-molecule screen for phospholamban modulators, Thomas said.

Thus far, the assay has been applied primarily to screening for cardiovascular disease therapies, but "assays for calcium pump activity might be relevant in other diseases," Thomas said.

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