ARRA-funded pilot project lays the foundation for DNA banking in stroke study
By Karen Eddleman
April 13, 2011
A patient is undergoing an MRI scan to look for signs of a stroke. Photo courtesy of NIH Image Bank.
Teresa Gonzalez considers herself lucky.
Two years ago, she was in the kitchen washing dishes as her husband Guillermo dried them. As they chatted, a dinner plate slipped from Teresa’s hand and shattered on the floor. Alarmed, Guillermo saw that the right side of his wife’s face was sagging and motionless. He caught her as she slumped to the floor.
Teresa awoke in the hospital unable to move the right side of her body. “I couldn’t believe it, but the MRI doesn’t lie. I had a stroke even though I was only 42.” Teresa had had a small subcortical stroke, which occurs when the blood flow through small arteries in the brain is blocked. Because Guillermo wasted no time calling 9-1-1, Teresa was eligible to receive a clot-busting drug called tissue plasminogen activator ( t-PA) at a designated stroke center. “I think I am alive today and escaped without disability because I got t-PA so quickly,” Teresa said.
Teresa wasn’t out of the woods, though. Patients who have had one subcortical stroke are at great risk of having subsequent ones. The unfortunate results of the repeated insults to the brain often are paralysis and dementia. To try to prevent further strokes, Teresa and her doctor experimented with a variety of drugs to thin her blood and to inhibit the “stickiness” of her platelets (i.e., the blood cells responsible for forming clots to stop bleeding). But finding the right drug at the right dose was a tricky proposition—too high a dose and she could experience uncontrollable bleeding from a wound or in her brain or gastrointestinal system. Too low a dose, and she would be at risk of another stroke. The process required frequent blood testing to adjust the drug regimen, and even changes in diet could upset the delicate balance.
“It seemed as if keeping my blood clotting in the safe range was just trial and error,” Teresa worried. “Isn’t there a better way?”
Teresa’s question is relevant to many Americans who have had strokes or are at risk of stroke. According to the Centers for Disease Control and Prevention, stroke is the third leading cause of death and a major cause of disabilities among adults in the United States. About 137,000 Americans die of stroke every year. Subcortical strokes, also called lacunar strokes, account for more than 27 percent of all ischemic strokes (the most common type of stroke). Hispanics and Blacks are at much greater risk of small subcortical strokes than are other populations, and they are more likely to suffer severe consequences from such strokes.
Custom-Fitting Drug Treatment to the Individual
The research focus of Julie Johnson, Pharm.D., at the University of Florida is on human genes that affect patients’ responses to drugs used to prevent stroke and treat high blood pressure. Photo by Sarah Kiewel, University of Florida.
Julie Johnson, Pharm.D., professor and chair of pharmacotherapy and translational research and the Director of the Center for Pharmacogenomics at the University of Florida, is helping to personalize drug regimens to prevent repeat subcortical strokes.
Johnson is working with a group of scientists in the Pharmacogenomics Research Network (PGRN) at the National Institutes of Health. PGRN researchers are using pharmacogenomics—studies of how people’s genetic makeup affects the way they respond to drugs—to try to predict which medicines will work best at which doses and with the fewest adverse side effects for a given person. Johnson and the PGRN have already achieved considerable success in several studies.
“One of our PGRN goals is to incorporate pharmacogenomics aspects into ongoing studies,” says Johnson. “The network can facilitate DNA collection to expand the scope of scientific questions and explore the genetic basis for differing drug responses.”
Thanks to a jump start from a modest amount of funding from the National Institute of General Medical Sciences (NIGMS) that was made available through the American Recovery and Reinvestment Act of 2009 (ARRA), Johnson and her colleagues are laying the groundwork to test hypotheses on the interaction of different genes with stroke prevention drugs. Armed with such information, doctors may in the future be able to personalize their patients’ drug regimens to prevent recurrent subcortical strokes.
ARRA-Funded Pilot Project Explores Pharmacogenomics Approach
A major study called the Secondary Prevention of Small Subcortical Strokes (SPS3) is testing whether taking both aspirin and clopidogrel (Plavix) will be more effective in preventing another stroke than just taking aspirin alone. This study also is seeking information about the best ways to control blood pressure after a stroke.
Under the leadership of principal investigator Oscar Benavente, M.D., professor of neurology and
Research Director of Cerebrovascular Health and Stroke at the University of British Columbia and Vancouver Coastal Health, SPS3 is enrolling 3,000 participants from more than 60 different medical centers around the United States, Canada, Latin America, and Europe. The aim is to include at least 20 percent Hispanics because of their high risk for this type of stroke.
With ARRA support, Johnson and her co-principal investigator Alan Shuldiner, M.D., professor of medicine and Associate Dean and Director of the Program in Personalized and Genomic Medicine at the University of Maryland School of Medicine, piggybacked a small pharmacogenomics study onto the SPS3 trial. Under the auspices of PGRN, Shuldiner leads a research group called Amish Pharmacogenomics of Antiplatelet Intervention (PAPI) Study, and Johnson heads up the Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study.
“The pilot allowed the PEAR and PAPI investigators to establish collaborations with the SPS3 investigators and provide some evidence that genetic samples and data could be collected,” Johnson explains. “With ARRA funding, we were able to add a pharmacogenomics component at 10 study sites and collect and store 500 DNA samples from study participants.”
Scaling Up from the Pilot Study
The success of the NIGMS pilot study bolstered Johnson and Shuldiner’s application for additional funding from the National Institute of Neurological Disorders and Stroke (NINDS) and led to an award of more than $700,000 to extend their work on identifying genes that lead to differing responses to drugs for preventing repeat subcortical strokes.
“Strokes are fairly common, but little has been done in the way of genetic sample collection,” Johnson says. “Our major goal is to build a DNA bank with 2,000 samples collected from as many SPS3 participants as possible.” The investigators are preparing documents that will allow the pharmacogenomics samples to be collected at dozens of study sites, and they are putting in place the logistics to establish the central DNA bank.
“We are ramping up to initiate the pharmacogenomics study at many of the SPS3 study sites and to start collecting samples right away. Once the DNA samples are collected and stored, we can garner additional support to start looking for genetic variation that could explain differences in how patients respond to therapy with aspirin or clopidogrel or to medicines for treating high blood pressure,” Johnson says. “In the future, many scientific opportunities will come to light. The important thing at the moment is to get the samples and collect the data that can be used to help patients and their doctors identify the best way to protect against repeat strokes.”
Building on Success
ARRA funding opened the door for Johnson and Shuldiner by allowing them to prove that pharmacogenomics samples and data could be collected in the context of a major clinical trial, and the PGRN provided a supportive environment to nurture collaboration between pharmacogenomics researchers and clinical trial investigators. The successful pilot study supported by ARRA funds led to a larger grant from NINDS to take the study to a whole new level. “We are accomplishing things as a network that could not be done by individual investigators,” Johnson asserts. “All of what we learn from SPS3—the first-ever study to focus on subcortical stroke patients—will be important.”
Recovery Act Investment: “Pharmacogenomic Evaluation of Antihypertensive Responses”; Julie A. Johnson; University of Florida; 2009: $149,635 (3U01GM074492-05S1). Funded by the National Institute of General Medical Sciences.
Related Study: “Secondary Prevention of Small Subcortical Strokes Trial (SPS3),” ClinicalTrials.gov identifier NCT00059306.
