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Nov 1, 2010 (Vol. 30, No. 19)

Microarray Technology Moves to the Fore

Improved and Reconfigured Platforms Help Researchers Maximize Genomics Studies

  • Microarray technology has come of age as a powerful approach to revealing the genome and its dynamic expression through the application of gene-hybridization or gene-expression microarrays. While the former are aimed at detecting the presence of specific genes in a sample, the latter are designed to measure the level of activity of genes in particular tissues.

    Because gene-expression microarrays display the transcriptional activity of the tissue from which they are derived, they have the potential to reveal new and unanticipated gene functions, including unforeseen disease subtypes, new diagnostic markers, and mechanisms determining disease susceptibility.

    As the technology has developed over the years, earlier problems of lack of consistency and repeatability have been addressed, and the data generated by these investigations is much more robust and comprehensive than in the early discovery period of this technology. A number of companies are moving forward on different fronts to make these improved and reconfigured platforms available to their customer base.

    Much of the activity in microarray design is based on the custom requirements of investigators. The starting point is the basic material used in building microarrays, mainly oligonucleotides and peptides. Sigma Life Sciences, a division of Sigma-Aldrich, has substantial involvement in this technology with facilities throughout the world dedicated to their manufacture, according to Stacey Hoge, product manager for custom DNA and PEPscreen, and Carlos I. Martinez, Ph.D., head of global technology development.

    “Given that we have many manufacturing sites, it is important that our technology be normalized and harmonized,” Hoge explains. “Everything is made to order, but at the same time, we have to rapidly meet the needs of our customers.”

    Synthetic peptides can be important components of disease-monitoring technologies. Sigma produces overlapping peptides that represent strong HIV epitopes. They can be incorporated into 96-well microarrays and used to screen patient sera for HIV progression, as evidenced by the production of anti-HIV antibodies.

    “Frequently, customers are looking to improve the quality of printing when they design microarrays, so we may use an amine linkage to achieve better printing quality,” explains Dr. Martinez.

    Monitoring and repairing errors that may be inadvertently introduced into the sequences of the reagents is an important component of the Sigma services, especially since the work is time-sensitive. Peptides and oligonucleotides are quality controlled through the use of MALDI-TOF and electrospray ionization.

    “Analytical instrumentation is similar to the computer industry, in that it is constantly changing. The machines cost hundreds of thousands of dollars, so we can’t be constantly replacing them; however we are adding minor upgrades and improved software all the time.”

    In fact, the lifespan of a typical instrument is about 10 years. “The benefits of this evolving technology are greater simplicity and lower operating costs, but this requires orchestration because all our centers must have identical approaches.”

  • Oncology Microarrays

    Click Image To Enlarge +
    Almac Group, a Powered by Affymetrix partner, enables the transfer of biomarkers from research to the clinic with proprietary arrays using Affymetrix microarray technology, including the Xcel™ for biomarker discovery and Cancer DSA® for disease transcriptomes identification, and provides a range of prognostic tests for some of the most common types of cancer.

    Affymetrix offers platforms for DNA copy number, SNPs, and RNA-expression analysis, according to Dara Wright, vp for clinical marketing.

    “Recently, we commercialized the OncoScan FFPE Express cancer copy-number array service.” This platform is designed to profile FFPE samples on the company’s GeneChip microarray platform. These genetic signatures aid in clinical trial stratification and may ultimately lead to companion diagnostic and other clinical test development, Wright adds.

    The technology requires a modest quantity of input DNA and yields copy number, allelic ratio, and somatic mutation data from the samples. The intention is also to develop an off-the-shelf product that customers can run in their own lab.

    The challenges inherent in building microarray-based tests that can achieve FDA approval are well-known. “There is a growing body of literature and clinical studies detailing how multiparametric gene signatures can significantly improve diagnostic yield as compared to traditional techniques such as karyotyping.

    “There is a consensus building in the industry concerning the optimal approach to validation and development of oversight guidelines for lab-based interpretations of complex findings. I believe it is likely that many new genetic tests for cancer diagnosis and prognosis will reach commercialization in the next few years.”

    To expedite the improvement of array-based clinical assays, the company has introduced the Powered by Affymetrix Program, which enables partners to build and commercialize tests for disease diagnosis and stratification.

    A collaboration with The Medical Prognosis Institute (MPI) to develop microarray-based tests to determine which cancer patients have the greatest likelihood of benefiting from a particular drug exemplifies this approach. Using the FDA-approved Affymetrix GeneChip® System 3000 Dx v.2 and custom microarrays, MPI’s Drug Response Predictor pairs its algorithms with a proven platform to help guide clinical validation and patient treatment.

    In another partnership, Affymetrix is working with Signature Diagnostics, a German clinical diagnostic company with two microarray-based tests for colorectal cancer. Signature Diagnostics plans to launch these tests in Europe and will subsequently seek U.S. regulatory approval.

    As a component of its partnership with the scientific community, Affymetrix participates in relevant scientific societies, consortia, and government-sponsored symposia. Through these efforts, the company helps promote the application and standardization of microarray technologies.

    One recent example is its work with the MicroArray Quality Control (MAQC-II) initiative. “This is the second phase of a study that involved more than 400 representatives working to establish best practices for development and validation of predictive models based on microarray gene expression and genotyping data for personalized medicine.” 

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