Drug repositioning– taking known drugs and identifying new applications for them–is an attractive concept for speeding up the process of bringing drugs to human testing for unmet medical needs.
In a new study, published online Dec. 11 in the Annals of Clinical and Translational Neurology, University of Iowa researchers led by Alexander Bassuk, MD, PhD, professor of pediatrics and neurology with UI Health Care, use a multidisciplinary strategy that combines gene expression profiling and bioinformatics to identify a list of around 90 drugs, all of which already are approved by the Food and Drug Administration (FDA) for use in people or animals, that may also have potential as anti-seizure treatments.
“Taking a new look at medicines that are already approved for clinical use may help identify treatments that could reduce seizures and improve the quality of life for people with epilepsy who have been unable to find effective therapies,” said Vicky Whittemore, PhD, program director at the National Institute of Neurological Disorders and Stroke (NINDS), which funded the study.
The UI team tested candidate drugs from the list in a zebrafish model of seizures and found that three–a diabetes drug, a hypertension medication, and an antiparasitic therapy– significantly reduced seizure-like movement in the fish.
“The long timeline and high cost of drug development is a particularly acute issue for a life-altering disease like epilepsy where up to one-third of patients are not completely helped by the medications we currently have,” says Bassuk, who also is division director of pediatric neurology and a member of the Iowa Neuroscience Institute (INI). “The question here was could we use novel techniques to identify potential new treatments more quickly than via traditional drug discovery and development routes.”
A unique starting point
A unique feature of the UI study, according to Bassuk, was the ability to use live human brain tissue from patients with epilepsy as a starting point.
The tissue was collected by UI neurosurgeons (led by Matthew Howard, MD, UI professor and DEO of neurosurgery) from six patients undergoing specialized surgery to remove brain areas causing seizures. This type of surgery is a treatment option for people with epilepsy whose seizures can’t be controlled by medications. The patients agreed to allow use of the tissue in the study. During the surgery, the neurosurgeons placed electrodes on the patient’s brain to determine which areas to remove. These electrodes also allowed the surgeons to distinguish which parts of the removed tissue were seizing and which areas, also contained within the removed tissue, were behaving normally.
Computational psychiatry researchers Jacob Michaelson, PhD, and Leo Brueggeman analyzed gene expression for more than 25,000 genes the brain tissue, and discovered strikingly different expression patterns in the diseased (seizing) tissue compared to non-seizing tissue. They then compared these expression signatures to a large database known as a connectivity map, which contains gene expression patterns produced by the action of drugs on cells. The comparison identified 184 compounds that were deemed potentially therapeutic because they produced patterns that were essentially the reverse of the seizure expression pattern.