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Apr 15, 2009 (Vol. 29, No. 8)

Focused Assays Lead to More Potent Drugs

Label-Free Remains No.1 Cell-Based Trend, but Electrophysiology Is Not Far Behind

  • Off-Target Effects

    xCELLigence™, a cell-based assay system codeveloped by ACEA Biosciences and Roche Applied Science, combines microelectronics and cell biology to provide a label-free process to monitor live cells under physiological conditions. A disposable 96-well E plate contains a microelectronic biosensor in each well. “The cells interact with the gold microelectrodes, leading to changes in impedance,” explains Yama Abassi, Ph.D., senior director, cell biology, ACEA. Each change in the cells’ status, i.e., adhesion, cytotoxicity, cell proliferation, cell-cell interactions, or morphological changes, alters the impedance measurements, and therefore, can be quickly detected in real-time.

    Eliminating labels brings the cells closer to physiological conditions and avoids costs associated with radioactive dyes. The microelectronic readout is noninvasive, so cells are not destroyed and can be continuously monitored. This, says Dr. Abassi, allows the user to build a kinetic profile of the experiment. “It gives us a quality-control picture of how the cells are behaving inside the wells and then when we treat the cells with a particular compound, we can observe if the response is immediate. This could not be accomplished by standard endpoint assays.”

    Recent research efforts have been focused on two areas: morphological profiling and safety pharmacology. “We’ve noticed that, when we grow cells and add compounds, we get specific genetic signature patterns. These are dependent on the mechanism of action of the compound,” Dr. Abassi states.

    Safety pharmacology efforts are focused on cardiotoxicity effects. His group uses embryonic stem cells differentiated into cardiomyocytes and monitors the effects of pro-arrhythmic compounds on these cells. This is significant because, according to Dr. Abassi, “almost 30 percent of lead compounds being developed ultimately fail because of some type of cardiotoxicity. It’s a huge problem and people are looking for ways to predict it much earlier in the drug discovery pipeline.”

  • Label-Free HT Platform

    Click Image To Enlarge +
    MDS Analytical Technologies' CellKey platform uses a noninvasive, impedance-based approach that measures changes in impedance in response to activation of signaling pathways within cells.

    Label-free systems can generate fewer false positives and reduce nonspecific effects that occur in labeled assays, states Debra Gallant, product marketing manager, MDS Analytical Technologies. The company’s CellKey™ platforms (96- and 384-well formats) use a noninvasive, impedance-based approach that measures changes in impedance in response to activation of signaling pathways within cells.

    A monolayer of cells (adherent, suspension, or primary) is seeded onto a  microplate that has electrodes on the bottom of the wells. A small voltage is applied through the electrodes: low frequency passes between the cells, high frequency goes through cell membranes. Impedance can be altered by cell adhesion, morphology, volume, and changes in the interaction between cells.

    “This platform is really an enabling tool for measuring endogenous receptors of primary cell types. The resulting data is biorelevant. The industry has recognized that it needs drug discovery assays that are more physiologically relevant in order to help it prioritize its lead compounds sooner and more effectively,” adds Gallant.

    Another key feature to this system is onboard fluidics, which enables the simultaneous measurement of cell response while adding a compound. CellKey response profiles assist in understanding the underlying pathways activated upon compound or ligand addition, for example, differentiating between different classes of GPCRs. The profiles can also be used in the later stages of lead identification to study effects of different inhibitors and to gain more detailed information on the mechanism of action of lead compounds. Additional applications being developed for the CellKey system include ion-channel analysis and the use of additional primary cell types.

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