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NIH Awards Cyntellect Grant to Apply Transfection, Imaging System to Combinatorial siRNA Libraries


Cyntellect, together with researchers from the University of Texas Medical Branch, have recently launched a project to use the company's laser-based transfection and imaging system to screen combinatorial siRNA libraries.

The work is being supported by a one-year grant from the National Institute of General Medical Sciences worth $338,000, and is expected to provide Cyntellect with data to woo potential big pharma customers interested in the LEAP system.

The transfection/imaging system, called LEAP for laser-enabling analysis and processing, uses a laser to temporarily permeabilize cells so that a variety of molecules, including siRNAs, can be transfected via a process termed opto-injection. The system's laser can also be used to destroy untransfected cells, so that researchers end up with a pure set of transfected cells.

According to Fred Koller, president and CTO of Cyntellect, the partnership with UTMB stems from a previous relationship between the company and researchers at the institute, including David Gorenstein.

"They've done some preliminary work where they've shown that some of these modifications can be dramatically more effective than standard siRNAs, [but] they haven't been able to screen enough of [the modified siRNAs] to really dig into a [combinatorial] library."

Gorenstein's team has developed novel modifications for extending the plasma half-life and binding capabilities of nucleic acids, which they have started applying to siRNAs, but lacked the ability to conduct high-throughput screening, Koller told RNAi News this week.

"They've done some preliminary work where they've shown that some of these modifications can be dramatically more effective than standard siRNAs, [but] they haven't been able to screen enough of [the modified siRNAs] to really dig into a [combinatorial] library," he said. "We had a relationship with them in the past … [as well as] the … expertise for cell-based assays. [So] we decided to write a grant with them where we would explore the nucleic acid chemical modifications they had developed … to discover if some of these modified chemical approaches to nucleic acids can improve siRNAs in terms of specificity, toxicity, and knockdown."

According to the grant abstract, the UTMB researchers will generate a bead-based combinatorial thio-modified siRNA library, which will be screened using the LEAP system. "Hits will be migrated to leads based on confirmatory screening and secondary assays," the grant's abstract states. "A focused second-generation combinatorial library will then be generated and screened based on first-generation results, again resulting in hits to be migrated to leads based on follow-up secondary assays."

Koller noted that the initial screens will focus on the cell-cycle regulator PLK-1, which was chosen because it is both relevant to drug discovery for its role in cancer and because Cyntellect already has an assay for it.

"We're not trying to develop a therapeutic for cancer specifically in this project," he noted, "but we have assays for it and know that it works."

Once this work is completed, Koller said that Cyntellect and the UTMB team plan to move into additional studies that will "follow up on … additional chemistry modifications, [and make] sure that the modifications that come out of this program are broadly applicable to a variety of targets and a variety of cell types."

The grant abstract notes that later-stage work will "focus on additional target genes and cell lines, including influenza and host immunomodulatory genes with utility in infectious disease research and treatment."

Ultimately, Koller expects the collaboration with UTMB to lead to "improved siRNA chemistries for in vitro use … that have advantages over existing chemistries out there in terms of reduced toxicity, improved specificity, and lower doses required to get gene silencing."

Additionally, the project is expected to yield data demonstrating the effectiveness of the LEAP system, which was launched in August.

"We've been approached by a number of big pharma companies that are interested in siRNA library screening and this project … puts us on a path where we'll be generating the kind of data that those types of customers would be interested in," Koller noted.

— Doug Macron ([email protected])

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