A Translational Paradigm for the Preclinical Evaluation of the Stroke Neuroprotectant Tat-NR2B9c in Gyrencephalic Nonhuman Primates

Nonhuman primates treated with a neuroprotectant after stroke showed outcomes that correctly anticipated those of a corresponding human trial. Monkey Do, Human Do Much has been written about the high costs of therapeutics discovery and the glaring gaps in the translation of new treatments from preclinical models to clinical use. Drugs for the treatment of stroke might be the poster child for such translational mishaps. Now, Cook et al. show that nonhuman primates treated with a neuroprotectant after stroke display outcomes that mimic those of a corresponding clinical trial in human subjects. A variety of explanations have been proposed for why treatments that successfully achieve neuroprotection in animals fail to translate to patients, including physiological differences between the brains of rodents and humans and the inability to reproduce strict laboratory conditions in clinical trials. Regardless of the reasons, the statistics are grim: According to the World Health Organization, among the 15 million people who suffer stroke worldwide each year, 5 million die and another 5 million become disabled. Thrombolytic agents, such as recombinant tissue-type plasminogen activator, are the only widely approved therapy for acute stroke, and treatment must occur within 3 hours. To develop an experimental paradigm that faithfully predicts the safety and efficacy of putative neuroprotectants in stroke patients, the authors tested a neuroprotective compound, Tat-NR2B9c, in high-order gyrencephalic nonhuman primates that share genetic, anatomical, and behavioral similarities with humans. The experimental protocol retained the properties of a then-ongoing clinical trial in human subjects called ENACT (Evaluating Neuroprotection in Aneurysm Coiling Therapy), which tested whether Tat-NR2B9c could reduce strokes in patients undergoing endovascular repair of an intracranial aneurysm, a procedure that has been shown by imaging methods to cause small ischemic strokes in the vast majority of patients. As visualized by two kinds of magnetic resonance imaging, primates treated with the drug after stroke onset displayed a reduction in the number and volume of strokes—an outcome that anticipated those of the corresponding human trial. Thus, this primate model and preclinical study design may permit predictive evaluation of promising neuroprotectants before testing in patients. Over decades, all attempts to translate acute stroke neuroprotectants from discovery in lower-order species to human clinical use have failed. This raised concerns about the predictive validity of preclinical studies in animals for outcomes in human stroke trials. To bridge this translational gap, we used high-order gyrencephalic nonhuman primates subjected to an experimental protocol that mimicked that of a corresponding, separately reported, clinical trial in which the human subjects underwent endovascular cerebral aneurysm repair. Both placebo-controlled studies tested neuroprotection by Tat-NR2B9c, a prospective therapeutic compound, in anesthetized subjects. Embolic strokes were produced by small intra-arterial emboli caused by the endovascular procedure. We show that primates treated with Tat-NR2B9c after the onset of embolic strokes exhibited significantly reduced numbers and volumes of strokes, as visualized by diffusion- and T2-weighted magnetic resonance imaging. These results correctly anticipated the outcome of the corresponding human trial, thus validating this study design as a predictor of neuroprotective efficacy in humans. This strategy may facilitate the evaluation of promising neuroprotectants before undertaking similar studies in human subjects.