Researchers have identified uric acid as a potential therapy to enhance recovery from acute ischemic stroke using a new method for conducting preclinical animal research. In the study, researchers from the National Institutes of Health’s Stroke Preclinical Assessment Network (SPAN)(link is external) rigorously tested the effectiveness of six novel therapies in reducing ischemic brain injury in rodents using strategies normally reserved for clinical studies in humans. The results suggest that uric acid warrants further investigation in additional studies, and potentially human clinical trials. The study was published in Science Translational Medicine(link is external).
Ischemic stroke, a leading cause of disability and death in the United States, occurs when a blood clot or other blockage in an artery cuts off blood supply to the brain. Current treatments are aimed at removing the clot by dissolving it with blood-thinners, surgically removing it from the blood vessel, or a combination of both.
Although these treatments help patients recover, scientists are seeking a therapy that could protect the brain from damage, known as a cerebroprotectant, that occurs before or during the restoration of blood flow. While previous preclinical studies in animals have identified numerous promising therapies, they failed to translate to human stroke patients in subsequent clinical trials. Many findings also did not replicate in other laboratories.
“We were faced with a critical need to redesign the entire preclinical approach,” said Francesca Bosetti, Ph.D., Pharm.D., program director at NINDS. “SPAN successfully applied well known clinical research practices to a preclinical trial—randomization, pre-determined sample sizes, treatment masking, blinded analysis, and efforts to make results reproducible in other laboratories.”
In the current study, six candidate therapies were selected based on prior research showing evidence that they could potentially treat stroke. Animals were randomly assigned to treatment and researchers from six different labs tested one of the therapies or a placebo. The efficacy of each treatment was assessed by giving animals a series of behavioral tests. After collecting these data, researchers used a new statistical method to evaluate the therapies at four points in the testing process. They also measured MRI brain scans of lesion volumes. Based on the test results, treatments that failed to show sufficient efficacy were dropped.
In addition to incorporating scientific rigor into preclinical testing, researchers used animal models that resembled typical stroke patients. The study included young mice and rats, aging mice, mice with diet-induced obesity or hyperglycemia, and rats with spontaneous hypertension, with equal numbers of males and females.
“SPAN gives us a head start in screening lots of stroke therapies, and rapidly and efficiently finding drugs that have a higher likelihood of working in human clinical trials,” said Patrick D. Lyden, M.D., professor of physiology and neuroscience at the Zilkha Neurogenetic Institute and professor in the Department of Neurology at the USC Keck School of Medicine, Los Angeles, and principal investigator of the SPAN coordinating center.
Uric acid was the only candidate that passed the efficacy boundary through all phases of analysis. The other interventions, which included four drugs approved by the U.S. Food and Drug Administration to treat other conditions and remote ischemic conditioning, an experimental medical procedure, were dropped after the second or third evaluation.
Uric acid has previously been tested in stroke patients, but not in combination with the clot removal treatment modeled by the study, suggesting that the drug could do well in future trials. However, investigators recommend further testing in animal models before clinical trials in humans.
In the next research phase, which began earlier this year, the SPAN network will expand to include more testing sites and evaluate five additional cerebroprotective interventions.
“SPAN is a collaborative effort by many labs to document reproducible effects in animal models of stroke that mimic treatments in patients,” said Walter J. Koroshetz, M.D., director of NIH’s National Institute of Neurological Disorders and Stroke (NINDS), which funds SPAN. “We now have a feasible preclinical research method to help identify therapies with a higher chance of success in clinical trials.”
SPAN is composed of a coordinating center at the University of Southern California, Los Angeles, and six research laboratories at Johns Hopkins University, Baltimore; Massachusetts General Hospital, Boston, Yale University, New Haven, Connecticut; the Medical College of Georgia at Augusta University; the University of Iowa, Iowa City; and the University of Texas Health Science Center at Houston.
The study was supported in part by the NINDS (U24NS113452, U01NS113356, U01NS113443, U01NS113445, U01NS113388, U01NS113451,U01NS113444, R01NS099455, R01NS112511, R01NS110378, R01NS117565, R01NS102583, R01NS109910), the National Heart Lung and Blood Institute (R35HL139926), National Center for Advancing Translational Sciences (UL1TR001881), and the National Institute of Biomedical Imaging and Bioengineering (P41EB015922). Author Ryan P. Cabeen is supported in part the Chan Zuckerberg Initiative. Aging mice were provided by the National Institute of Aging’s aged rodent colonies.