Enrique Leira - US grants

PROJECT SUMMARY Stroke is the most common contributor to disability in the United States (US), with over 800,000 people affected each year. In addition to treatment with intravenous recombinant tissue plasminogen activator (rtPA), endovascular mechanical thrombectomy (MT) is now the standard of care for patients with a stroke due to proximal arterial occlusion. Unlike rtPA, however, MT is available at only a limited number of tertiary centers, with stringent time-dependent effect tied to viable ischemic penumbra. As a result, many patients in rural or congested areas need rapid transfer to a tertiary center capable of delivering MT while undergoing intravenous rtPA infusion by Helicopter Emergency Medical Services (HEMS). There is thus a significant unmet need to develop neuroprotective interventions that promote patient eligibility for MT after HEMS. A significant barrier to progress, however, is concern of whether current animal stroke models adequately translate the effect of neuroprotective interventions on an ischemic brain receiving rtPA during HEMS evacuation. That concern is justified by the uniqueness of the HEMS physiological environment, with multiple physical factors such as hypobaric changes, low frequency vibration, three-axis acceleration, and extreme noise. These physical factors may affect ischemic brain receiving rtPA in multiple and opposing ways, such as decreased oxygenation in the penumbra, enhanced or decreased clot lytic effect of rtPA, increased blood-brain-barrier (BBB) permeability and raised blood pressure. There is therefore a critical need to clarify and quantify the effect of these factors on neurological outcomes, in order to ensure that preclinical animal stroke models rigorously account for the unique physiological HEMS environment. The objective of this proposal is to measure the potential effect of HEMS physical factors on ischemic brain with respect to rtPA-reperfusion, infarct size and BBB permeability. We will use a novel experimental approach that combines a traditional stroke animal model with actual helicopter transport and vibration simulation. We have a multidisciplinary team of animal researchers and engineering, with access to a dedicated Mi2 helicopter that has been adapted and certified as a flying research platform. Mice/rats undergoing an embolic stroke will be randomized to receive the rtPA infusion simultaneously either in an actual helicopter flight, vibration simulator, or under ground-based conditions. Outcome measures will include measures of rtPA activity, cerebral blood flow, infarction size and hemorrhagic transformation, and BBB permeability at 48h and sensorimotor neurological outcome measures at 7 days, all of which will be correlated with helicopter-generated factors such as vibration, acceleration and altitude. We anticipate that this work will meaningfully transform the field of acute stroke care by understanding the overall effect of HEMS in the ischemic brain. This will lead to the establishment of adequate animal models to facilitate intervention research to improve the outcomes of patients during this critical early setting.

The University of Iowa (UI) Regional Stroke Research Network meets the goal of NIH StrokeNet in maximizing efficiencies to develop, promote, and conduct high quality multi-site clinical trials testing promising interventions in stroke prevention, treatment, and recovery. The current proposal builds on the rich tradition of the UI as a leader in both developing and conducting NINDS-sponsored research, The long-term goal of this proposal is to improve the outcomes of the 800,000 Americans who suffer a stroke every year, particularly those subjected to disparities in health outcomes due to geographically underserved areas. Our proposal's immediate goals are to improve the collective network recruitment efficiency and generalizability of NINDS- sponsored trials by facilitating enrollment of subjects with geographical barriers to participation. Specifically, we aim to increase the number of efficient stroke interventions that can be applied to the vast majority of patients in the US. With that goal in mind, we propose to maintain the UIRCC as an Upper Midwest regional research network efficient in recruiting subjects in NINDS- funded stroke trials. The UIRCC is an already operational infrastructure of 14 trial-ready hospitals in Iowa, Nebraska, and North Dakota that enables enrollment of Americans that have been traditionally challenging to include in trials due to their geographically location. At the same time, the UIRCC will continue to engage a multidisciplinary team of translational researchers to generate innovative research proposals that will lead to multicenter clinical trials through StrokeNet. .

The University of Iowa Preclinical assessment Network (UIowa-SPAN) meets the goal of the NIH in maximizing efficiencies to develop and conduct rigorous pre-clinical comparative studies of neuroprotection in the context of stroke reperfusion. The current proposal builds on the rich tradition of the UIowa as a leader in preclinical and clinical NINDS-sponsored stroke research. This infrastructure brings together basic cerebrovascular scientists with vascular neurologists and clinical trialists to conduct rigorous animal trials of ischemia-reperfusion. We will capitalize on our experience using both male/female animals, co-morbidities (e.g. hyperlipidemia), combined with a rigorous methodology to minimize biases, including randomization, blinding, intention-to -treat analyses and independent outcome adjudications. Our proposal?s immediate goal is to advance the field of synergistic neuroprotective interventions by allowing uric acid (UA) progress from comparative animal experiments into phase II trials conducted in a future StrokeNet-developed research MT platform. Specifically, this proposal incorporates UA as one of the therapies to be tested through this preclinical assessment network. The free-radical (peroxynitrite) scavenger action of UA is crucial to minimize the brain reperfusion injury and lack of reflow that occurs after MT. UA has a strong record of efficacy in animals within STAIR/RIGOR guidelines, as well as an excellent record of safety and preliminary efficacy in patients treated with MT. Intravenous infusions of UA will be compared against the other candidate molecules in SPAN through blinded, randomized, adaptive experiments using the animals models and co-morbidities deemed necessary by the SPAN coordinating center. The proposal may have significant clinical implications by improving the outcomes of those Americans who suffer a stroke and require treatment with mechanical thrombectomy (MT).