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Illumavista Nets $370K from NIH to Develop TF-Focused SNAP Array Platform

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By Justin Petrone

The National Institutes of Health recently awarded Illumavista Biosciences $370,000 to develop a microarray platform for studying transcription factor binding.

Specifically, the Madison, Wis.-based firm received $150,000 to support a project entitled, "High-throughput method to assess SNP functionality in prostate cancer," and $268,168 to fund a second project, "Screening of FoxA1-ER-DNA disruptors for development of breast cancer therapeutic."

The first project is funded through Aug. 31, 2013, while the second is funded through Aug. 31, 2012.

Illumavista refers to its array platform as SNAP, which stands for specificity and affinity for proteins. The arrays are tiled to survey every possible binding site in the genome, according to the firm's website. Resulting fluorescence intensities correlate to solution binding affinities for each sequence, allowing users to predict where a molecule will bind in the genome.

The company envisions its approach will be useful in screening test compounds that can modulate the specificity of transcription factors involved in disease; discovering the DNA-binding preferences of a protein; examining the changes in specificity caused by a heterodimeric partner; designing sequence specific zinc finger nucleases; and designing therapeutics to disrupt transcription factor binding at a specific genomic location.

According to Christopher Warren, co-founder of the two-year-old firm, Illumavista will use the a portion of the grant money to support the development of a variation of its custom SNAP array platform, called SNP-SNAP, for use in research, as a diagnostic, and in drug development.

"We are using SNP-SNAP arrays to find out which SNPs affect transcription factor binding, with the idea that this is a major avenue of SNP function," he told BioArray News this week.

Warren said that the new company, which received no investment prior to the recent grants, is in the process of setting up operations and should be able to offer customers access to its platform via a service in the beginning of next year.

The company also plans to make assay kits available to customers later in 2012, he said.

"These are custom designed arrays made specifically to look at how transcription factors bind, not classic SNP arrays," Warren said. He added that the company's assay is designed to analyze cell lysate, nuclear lysate, and purified protein samples.

The arrays are manufactured by Roche NimbleGen, also based in Madison.

According to the abstract of the first grant, Illumavista plans to develop a SNP-SNAP array to evaluate the impact of SNPs associated with prostate cancer to generate or disrupt genomic binding sites for transcription factors involved in the disease.

The firm plans to create a chip containing 250,000 prostate cancer- related SNPs to assay transcription factors for their binding to these SNP DNA sequences. The resulting data will be correlated with prostate cancer incidence, and Illumavista believes its findings will "also relate prostate cancer-associated SNP function with cancer stage and aggressiveness."

Specifically, after designing the array and having it synthesized, Illumavista will examine the DNA binding specificity and affinity of 5 prostate cancer-related transcription factors, as purified proteins and from cell lysates on the SNP-SNAP array and annotate the human genome with the transcription factor binding differences due to SNPs. The results will be validated with chromatin immunoprecipitation, either on chip or ChIP-seq, in prostate cancer cells.

Warren noted that Immunavista prefers to use SNP arrays, rather than ChIP-on-chip or ChIP-seq, to study transcription factor binding, as ChIP-seq is "tedious and expensive," while the numbers of arrays required for large ChIP-on-chip studies make the approach "unfeasible."

He said that the company's approach in comparison "takes one array, is cheap and quick, and you can get your results within a few hours."

After obtaining SNP data from patients with prostate cancer, the firm will seek to determine if there is a statistically significant association of functional SNPs, which yielded differential binding of prostate cancer specific transcription factors on the SNP-SNAP array, with prostate cancer incidence.

According to Warren, the firm's approach to prostate cancer could be applied to any cancer type and disease model. "Let's consider a breast cancer model," he said. "We could use this array to identify which individuals would not benefit from tamoxifen based on certain SNPs."

Just as that information could be used to create companion diagnostics for certain drugs, he said, it could also be used to develop new therapies.

"As we know what transcription factors are affected by certain SNPs, we could develop drugs that target those SNPs," said Warren. "This would be a new class of drugs that are tailored for people who are not responsive to certain therapies."

The company's second project aims to use its original SNAP platform to study estrogen receptor α, a "major therapeutic target for breast cancer," the binding of which at target genes in breast cancer cells is guided by DNA-binding factor proteins such as FoxA1, according to the grant abstract.

Although the breast cancer drug tamoxifen — sold as Istubal, Nolvadex, and Valodex —is currently prescribed for suppressing ER-mediated gene regulation, the firm noted in the abstract that "resistance to tamoxifen occurs in most breast cancer patients within five years" and argued that a "major challenge in ERa drug design is the necessity to identify small-molecules that specifically target the molecular mechanisms of aberrant gene regulation in breast cancer, while leaving the physiological benefits of ERα action intact."

According to Illumavista, the "most critical interaction for ERα-mediated gene transcription occurs at its estrogen response element DNA site, and FoxA1 enhances ERα binding at EREs in breast cancer cells."

Illumavista therefore aims to use its SNAP arrays to study the DNA binding specificity of FoxA1- ERa in breast cancer, as well as the effect of disrupting FoxA1 enhancement of ERα binding with DNA-directed small molecules.

Specifically, the firm will use its arrays to characterize DNA binding preferences of FoxA1 from breast cancer cell lysates. Illumavista will then identify direct DNA binding sites of purified FoxA1 as well as potential protein-tethered FoxA1-DNA interactions in breast cancer cells. DNA-binding small molecules will then be designed to specifically target and disrupt the FoxA1-DNA interaction.

Ultimately, Illumavista hopes to develop an array-based screening platform to examine the ERα- FoxA1-DNA interaction and screen test compounds as targeted disruptors of this interaction, according to the abstract.


Have topics you'd like to see covered in BioArray News? Contact the editor at jpetrone [at] genomeweb [.] com

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