Translating promising preclinical neuroprotective therapies to human stroke trials.
ABSTRACT Stroke is the third leading cause of mortality and carries the greatest socioeconomic burden of disease in North America. Despite several promising therapies discovered in the preclinical setting, there have been no positive results in human stroke clinical trials to date. In this article, we review the potential causes for failure and discuss strategies that have been proposed to overcome the barrier to translation of stroke therapies. To improve the chance of success in future human stroke trials, we propose that therapies be tested in stroke models that closely resemble the human condition with molecular, imaging and functional outcomes that relate to outcomes utilized in clinical trials. These strategies include higher-order, old-world, nonhuman primate models of stroke with clinically relevant outcome measures. Although stroke neuroprotection has been looked upon pessimistically given the many failures in clinical trials to date, we propose that neuroprotection in humans is feasible and will be realized with rigorous translational science.
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ABSTRACT: Cellular fate of human neural stem cells (hNSCs) transplanted in the brain of nonhuman primates (NHPs) with no immunosuppression was determined at 22 and 24 months posttransplantation (PTx) regarding survival, differentiation, and tumorigenesis. Survival of hNSCs labeled with magnetic nanoparticles was successfully detected around injection sites in the brain at 22 months PTx by MRI. Histological examination of brain sections with H&E and Prussian blue staining at 24 months revealed that most of the grafted hNSCs were found located along the injection tract. Grafted hNSCs were found to differentiate into neurons at 24 months PTx. In addition, none of the grafted hNSCs were bromodeoxyuridine positive in the monkey brain, indicating that hNSCs did not replicate in the NHP brain and did not cause tumor formation. This study serves as a proof of principle and provides evidence that hNSCs transplanted in NHP brain could survive and differentiate into neurons in the absence of immunosuppression. It also serves as a preliminary study in our scheduled preclinical studies of hNSC transplantation in NHP stroke models.Cell Transplantation 01/2014; 24(2). DOI:10.3727/096368914X678526 · 3.57 Impact Factor
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ABSTRACT: Stroke is the third cause of death worldwide and the main cause of chronic, severe adult disability. We focus on acute ischaemic stroke, which accounts for approximately 80% of all strokes. The current therapy aims at restoring cerebral blood flow within a narrow time window in order to prevent damaging the “penumbra” which surrounds the infarct core. Intravenous thrombolysis remains the fundamental treatment worldwide, though not ideal for various restrictions and complications, limiting to 10% or less the percentage of patients treated within the appropriate time window. Neuroprotection is an alternative or adjunct approach to thrombolysis, targeting cerebral parenchyma in the acute ischaemic phase. Furthermore, neurorepair attempts to restore neuronal function in the after-stroke phase in those patients (treated or untreated) with significant impairment. In the past decades, the efficacy and safety of numerous candidate neuroprotective agents were showed in various animal stroke models. However, in clinical trials, promising pre-clinical studies have not been translated into positive outcomes. Our review will analyse the possible reasons for this failure and the new approaches and recommendations to overcome it, as well as novel strategies targeting additional events in ischaemia cascade. The combination of thrombolysis with pharmacological and non-pharmacological neuroprotective approaches has also been tested. Finally, the neurorepair strategy will be described with special emphasis on the role of cell-based therapies and ischaemic conditioning. Hopefully, the future therapy of ischaemic stroke will encompass a combination of neuroprotection (to stabilise penumbra), thrombolysis, antithrombotics (for secondary prevention) and neurorepair based on cell therapy plus rehabilitation.Pharmacology [?] Therapeutics 09/2014; 146. DOI:10.1016/j.pharmthera.2014.09.003 · 7.75 Impact Factor
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ABSTRACT: Purpose: We aimed to develop a nonhuman primate (NHP) stroke model for studies of secondary lesions in remote areas and to characterize its behavioral and neuroimaging features. Methods: Monkeys were either subjected to middle cerebral artery occlusion (MCAO) distal to the M1 branch (n = 17) or sham operation (n = 7). Neurological assessment and magnetic resonance imaging (MRI) were performed before and 1 week after operation. Results: After MCAO, six monkeys showed occlusion of the distal M1 segment and infarcts predominantly in the cortical and subcortical regions, without hippocampal and thalamic involvement. They had obvious neurological deficits. The other 11 monkeys showed blockage of the main trunk of the MCA, with infarcts extending into the hippocampus and thalamus, but no substantia nigra involvement. Their infarct volume were larger and neurological deficits were more severe than those after distal M1 occlusion. All sham-operated monkeys displayed normal behavior; however, MRI revealed small infarcts in three animals. Conclusions: MCAO or even sham operations might cause cerebral infarction in NHPs. Therefore, neurological assessment should be combined with MRI for screening candidate stroke models. Our model is suitable for studying secondary damage in remote regions, including the thalamus, hippocampus, and substantia nigra, after stroke.Restorative neurology and neuroscience 01/2015; DOI:10.3233/RNN-140440 · 4.18 Impact Factor