University of South Florida Department of Neurosurgery and Brain Repair faculty members have received a $2.6 million grant from the National Institutes of Health to investigate the potential for cells derived from human bone marrow to benefit post-stroke patients by repairing the blood-brain barrier (BBB). The BBB prevents harmful substances in circulating blood from entering the brain while allowing passage of needed substances.
According to the researchers, current treatment for ischemic stroke is limited to one FDA-approved drug, the serine protease tissue-type plasminogen activator (tPA) that to be effective must be administered during a three-hour window following a stroke.
"Although there are almost 800,000 stroke cases yearly in the US, less than three percent of patients benefit from tPA treatment," said Dr. Svitlana Garbuzova-Davis, assistant professor in the Department of Neurosurgery and Brain Repair and co-principal investigator on the grant. "Because of the drug's narrow three-hour therapeutic window, and its detrimental side effects that can exacerbate stroke injury and counteract the benefits provided by reperfusion of the occluded artery, new drugs are desperately needed."
According to Dr. Garbuzova-Davis, any treatment aimed at repairing stroke deficits should consider the pivotal role of BBB repair in order to maintain central nervous system (CNS) stability and enhance neuronal regeneration.
"Permanent BBB damage can lead to harmful serum protein leakage into ischemic brain tissue and may result in the formation of severe brain swelling in the hours and days following a stroke," she explained. "This damage could negatively influence CNS regenerative processes after a stroke."
Using animal models of stroke, the researchers will investigate how blood-brain barrier repair might mitigate the functional recovery in the stroke animals, and determine if BBB reconstitution can lead to positive therapeutic outcomes. Their research is aimed at discovering a potential mechanism underlying the BBB repair produced by stem cell transplantation.
"We believe that a regenerative mechanism involving the repair of the damaged BBB by endothelial progenitor cells (EPCs) derived from bone marrow is critical to the successful outcome of cell therapy in stroke," explained Dr. Garbuzova-Davis. "Whereas other cell-based technologies are largely designed to circumvent the BBB for delivery of cells or drugs from the periphery into the brain, we are taking a novel approach of repairing the BBB damage to lead to a therapeutic outcome for stroke victims."
According to the investigators, the site-specific EPC recruitment, followed by blood vessel repair processes, is important to exploiting BBB repair, a neglected therapeutic approach in stroke therapy. As these studies are designed to examine whether EPC transplantation extends the therapeutic window of tPA for stroke, the current research builds on the their long-standing goal of translating cell therapy from the laboratory to the clinic.
"If BBB restoration via EPC transplantation alone or in combination with tPA is proven effective, the researchers believe that direct clinical application of this cell therapy could help a large population of ischemic stroke patients who may have missed the limited 3-hour tPA window," explained Dr. Paul R. Sanberg, director of USF's Center of Excellence for Aging and Brain Repair.
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