Gene-Testing Machine for Doctors

A new device rapidly analyzes blood for medically relevant genetic variations.

A desktop instrument recently approved by the U.S. Food and Drug Administration might finally bring pharmacogenomic testing–the use of a patient’s genetic information for drug prescription decisions–to the mainstream. The device, made by Nanosphere, a startup based in Northbrook, IL, can, in a matter of hours, detect genetic variations in blood that modulate the effectiveness of some drugs. Dubbed Verigene, the technology employs a combination of microfluidics and nanotechnology, housed in a single plastic cartridge, to pull DNA from a blood sample and then screen it for the relevant sequences.

Simple testing: This disposable cartridge can detect genetic variations from blood samples. The circles lining the top and bottom are loaded with reagents for different chemical reactions. DNA is isolated from white blood cells and captured on a glass slide within the cartridge.

“We believe the benefit of our system is that this simple cartridge format could be run in any hospital, even a doctor’s office,” says William Moffitt, chief executive at Nanosphere. “We’re moving complex testing to the point of patient care.” Moffitt says Verigene is the first nanotechnology-based microfluidics product capable of analyzing DNA directly from a blood sample.

People can respond to drugs very differently, thanks in part to commonly occurring genetic variations in enzymes that metabolize some of the mostly highly prescribed compounds, such as heart medicines, pain medicines, and antidepressants. While doctors have widely adopted pharmacogenomic testing for prescribing some cancer drugs, such testing hasn’t yet taken hold for many other drugs whose effectiveness is modulated by genetics, including those for HIV, pain control, and epilepsy. The technology needed to detect these variations in patients has been available for years, but the process is often time-consuming and expensive. Physicians typically must send patients’ saliva or blood samples to a central lab, where the DNA is isolated, amplified, and analyzed. That process can take days or weeks.

“In some cases, it doesn’t matter if it takes a week to get a result. But in some cases we would like to have the information to choose a drug during the office visit, when the patient is right there,” says Howard McLeod, director of the Institute for Pharmacogenomics and Individualized Therapy at the University of North Carolina, Chapel Hill. “That way we can say, this drug is the one your DNA says will most likely be beneficial.”

The anticoagulant warfarin, for example, is frequently prescribed to prevent blood clots. But people metabolize the drug differently, meaning patients must be carefully monitored to make sure they don’t suffer dangerous bleeding. The FDA changed the drug’s label in 2007 to note that two specific genetic variations affect a patient’s sensitivity to the drug, but broad gene testing has not yet caught on. “Currently, available genotyping tests for warfarin pharmacogenomics require isolation of DNA from blood and testing in a molecular diagnostics laboratory certified for high-complexity testing,” says Karen Weck, director of the molecular genetics laboratory at the University of North Carolina, Chapel Hill.

Nanosphere is developing a test that can detect these variations in blood samples in an hour or two. A patient’s blood is injected into a disposable cartridge, which holds a glass slide dotted with DNA. The plastic frame also houses a system of microfluidics chambers containing the reagents for a number of chemical reactions. When the cartridge is inserted into the Verigene instrument, mechanical valves and air pressure mix the reagents in different chambers, triggering a series of reactions.

Magnetic beads first pull out white blood cells, which are burst open using sonic energy, releasing fragments of DNA. Everything but the DNA is then washed away, and a solution of these DNA fragments flows over the glass slide. Target DNA binds to spots on the slide that have been printed with DNA sequences complementary to those of the target sequence. Gold nanoparticles, about 13 nanometers in diameter, then attach to the other end of captured DNA fragments, sandwiching the target. Each gold nanoparticle is coated with silver, expanding the diameter to half a micron, thus allowing it to be easily detected when hit with light.

“If it works, this could be a convenient way for physicians and coagulation clinics to incorporate pharmacogenomic information into warfarin dosing,” says Weck. However, she adds, “the accuracy of the test should be carefully compared to more traditional molecular tests before it is widely used.” Nanosphere already has FDA approval for a warfarin test used in an older version of its system and plans to file for regulatory approval for its new test next year.

The company is also developing a pharmacogenomics test for use with the anticlotting drug Plavix, which is prescribed to people given heart stents. The drug must be metabolized into its active form, and scientists recently discovered that about 30 percent of Caucasians have a poorly functioning variant of the enzyme that metabolizes the drug and are thus less likely to benefit from it. While it’s currently possible to identify these patients through mail-order testing, “we want to know the answer before the patient goes home,” says Marc Sabatine, a cardiologist at Brigham and Women’s Hospital in Boston.

Nanosphere’s device is one of a number of microfluidics technologies in development for so-called “point of care” genetic testing–diagnostics that can be performed in the hospital or doctor’s office while the patient is there. Verigene, which was approved by the FDA in October, can come with different modules, ranging from $40,000 to $80,000, designed for different types of testing.

“You could have a version of our system in a molecular diagnostics lab running genetic assays, like those for cystic fibrosis and warfarin, or in a microbiology lab running virus assays, or in a stat lab for ER running tests, like the cardiac troponin test, a biomarker to diagnose heart attack, and pharmacogenomic testing for [Plavix metabolism],” says Moffitt. The Verigene system can also detect respiratory viruses, such as the H1N1 flu. Over the past month, the company has been installing the systems in medical centers ranging from typical community hospitals to large academic research hospitals.

Researchers hope the availability of this type of testing will enable the discovery of new applications in pharmacogenomic testing. “There are also drugs we use in [intensive care units] that would benefit from genetic-guided therapy, but because of the absence of technology [for quick pharmacogenomic] testing, no one is really trying,” says McLeod.

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