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Adapting Assays for Clinical Applications

By Larry Hand

April 1, 2008 | Sometimes, it helps to think smaller - or, in this case, less dense. The capability of DNA microarrays to produce copious amounts of data can make it difficult to extract clinically applicable meaning from assay studies. Instead of taking the macro look at gene expression analysis with high-density arrays, some researchers are using low- to mid-density arrays to develop tests for diagnostics or metabolic profiling. Rather than 1,000 or more elements per array, the lower density multiplex assays typically have two to 100 elements. Targeting a smaller number of analytes, such as biomarkers, allows researchers to hone in on applications ranging from heredity studies to drug metabolism to patient stratification. Pharmaceutical companies are hoping that biomarker efforts like these will both expedite the passage of new drugs to market and help determine which therapeutics will work with which patients.

"A disease marker shows us if somebody is sick or not, and if we have the right combination of markers, we will actually be able to identify the disease," says Guido Grentzmann, president of PBS PharmaBioServices in France. "A surrogate marker is a disease marker that would correlate with successful treatment of the disease. It will show the efficacy of the compound." Wendy Sanhai, a senior scientific advisor at the U.S. Food and Drug Administration (FDA), adds, "Patient selection is a key part of personalized medicine. Assays are being developed that can select the patients who would most likely respond to a particular drug."

One of the best known tests comes from Roche Diagnostics. Using Affymetrix GeneChip technology, the AmpliChip CYP450 microarray is Roche's first microarray for clinical applications. Clinical diagnostic laboratories can use the test to identify polymorphisms in two genes, CYP2D6 and CYP2C19, which play a major role in drug metabolism. These variants affect the rate at which an individual metabolizes drugs. Results of the test can guide a physician in choosing the best drug at the right dose for a patient, or tell the physician which drugs to avoid due to potential adverse reactions.
One company is combining technologies to come up with marketable DNA tests. Asper Biotech (Tartu, Estonia) offers tests that are microarray-based but also subjected to Arrayed Primer Extension (APEX) resequencing for rapid identification of mutations. APEX is carried out on a 2-dimensional array of oligonucleotides, and the DNA sample is amplified by PCR. From sample preparation to test results takes only four hours. Asper's tests are available for cancer, hereditary hearing loss, cystic fibrosis, and other needs.

Electronic Options
Electronic microarrays have allowed researchers to speed up the accurate detection of single nucleotide polymorphisms (SNPs) in DNA sequences. Hybridization can take several hours with conventional microarrays but less than a minute with electronic microarrays.

Osmetech Molecular Diagnostics (Pasadena, Calif.) uses electronics in its low-density positional microarrays. Its eSensor detection technology has DNA fragments attached to electrodes on the surface of a small circuit board. Each electrode detects a different DNA sequence. Finding the complementary sequence in the target DNA generates a characteristic electrical signal.

In January 2006, Osmetech received FDA approval for its cystic fibrosis carrier detection test and its eSensor 4800 DNA detection instrument platform. The company is pursuing development of its next-generation eSensor XT-8 instrument, which has the capacity to routinely run complex assays, including cytochrome P450 pharmacogenomic assays. It also has a higher chip density that enables wider gene mutation analysis.
On tap for the future for these technologies are higher sensitivity, higher specificity, and the capability to detect biomarkers from smaller samples. And, as is often the true test of translating research efforts into clinical use, lower costs and more user friendliness will be necessary for widespread use in clinical laboratories or physician's offices.

Larry Hand is editorial director at Insight Pharma Reports, a business unit of Cambridge Healthtech Institute. He can be reached at

Further Reading:
Multiplex Assays in Translational Medicine: Technologies, Applications, and Future Directions by Olivia Scaros (Insight Pharma Reports). For more information, go to


 This article appeared in Bio-IT World Magazine.
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