Companies to apply proprietary analytical technique to Alzheimer’s disease research

Back-scattering interferometry offers promise of revolutionizing screening for drugs that inhibit amyloid build-up

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MONTARA, Calif.—Using proprietary technology licensed from Vanderbilt University in 2007, Molecular Sensing Inc. (MSI) has entered into a research agreement with renowned Alzheimer's disease researcher Dr. Bart de Strooper of the VIB research institute of the Katholieke Universiteit Leuven in Belgium to use MSI's proprietary Back-Scattering Interferometry (BSI) technology to study ligand binding to the membrane-bound -secretase complex.

"We know that -secretase blocks the amyloid peptide which is the driving force of AD," de Strooper says. "What we are trying to understand is how -secretase binds to a number of very different substrates. Once the structure-function relationship is understood, we can target drug therapy and avoid side affects."

De Strooper notes that VIB maintains a "technology watch" group that looks for emerging technologies such as Molecular Sensing's BSI, which was developed by Darryl Bornhop and his group at Vanderbilt. MSI had created a number of prototypes to demonstrate the technology and established LEAP—the Life Science Early Access Program.

"LEAP is a fee-based early access program designed to provide customized collaboration partnerships with major laboratories in basic life sciences and pharmaceutical R&D," explains Scot Weinberger, MSI's president and CEO.

"Elucidation of the structure-function relationship of the active -secretase complex is important for understanding the basic biology and pathogenesis of AD. Development of APP-selective -secretase inhibitors is one of the major directions in AD therapeutics," says de Strooper.

The aim of the project is the characterization of the substrate recognition mechanism of the _-secretase complex and to screen for potential drug compounds that inhibit amyloid build-up. de Stooper adds that the financial details of the relationship are confidential and that the research work has just begun. Nevertheless, he thinks BSI "looks very promising" because it allows measurement of interactions that can't be done with any other technology.

"BSI is a breakthrough in molecular interaction assay technology, in particular, characterizing ligand binding to integral, membrane-bound proteins," says MSI's Weinberger. As reported by Bornhop, et al., in Science (September 2007), BSI technology uniquely enables homogeneous assays of molecular interactions at zeptomole sensitivity. Measurements are made in solution to determine affinity constants between associating molecules, free of coupling to spectroscopic labels or tethering to a chip surface.

Bornhop and his group used a simple optical train composed of a helium-neon laser, a microfluidic channel, and a position sensor to determine molecular binding interactions between proteins, ions and protein and small molecules and protein, with high-dynamic range dissociation constants (Kd spanning six decades) and unmatched sensitivity (picomolar Kd's and detection limits of 10,000s of molecules). The high sensitivity of back-scattering interferometry and small volumes of microfluidics allowed the entire calcium modulated protein (calmodulin) assay to be performed with 200 picomoles of solute. The analytical technique compares favorably with surface plasma resonance (SPR) and isothermal titration calorimetry (ITC), MSI data indicate, with BSI requiring less target protein, a smaller sample volume and less analysis time per sample while providing the best dynamic range.

In June 2008, MSI announced that it had entered into a LEAP agreement with Merck KGaA in Darmstadt, Germany, acting on behalf of its division for innovative prescription pharmaceuticals, Merck Serono, to evaluate BSI technology. BSI validated assays include protein binding to metal ions, drugs, peptides, or other proteins, antigen-antibody association and DNA-protein or DNA-DNA binding, in serum, cell lysates and cell free media with microliter sample volume and picomolar sensitivity.

Also in 2008, MSI signed a Cooperative Research and Development Agreement (CRADA) with the Centers for Disease Control's National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention (NCHSTP). The effort will use BSI technology as a platform for detection of infectious disease and typing of causative agents.


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