Steps to Translate Preconditioning from Basic Research to the Clinic
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REVIEW ARTICLE
Steps to Translate Preconditioning from Basic Research to the Clinic Frances R. Bahjat & Raffaella Gesuete & Mary P. Stenzel-Poore
Received: 25 September 2012 / Revised: 16 October 2012 / Accepted: 22 October 2012 / Published online: 2 November 2012 # Springer Science+Business Media New York 2012
Abstract Efforts to treat cardiovascular and cerebrovascular diseases often focus on the mitigation of ischemia–reperfusion (I/R) injury. Many treatments or “preconditioners” are known to provide substantial protection against I/R injury when administered prior to the event. Brief periods of ischemia itself have been validated as a means to achieve neuroprotection in many experimental disease settings, in multiple organ systems, and in multiple species suggesting a common pathway leading to tolerance. In addition, pharmacological agents that act as potent preconditioners have been described. Experimental induction of neuroprotection using these various preconditioning paradigms has provided a unique window into the brain's endogenous protective mechanisms. Moreover, preconditioning agents themselves hold significant promise as clinical-stage therapies for prevention of I/R injury. The aim of this article is to explore several key steps involved in the preclinical validation of preconditioning agents prior to the conduct of clinical studies in humans. Drug development is difficult, expensive, and relies on multifactorial analysis of data from diverse disciplines. Importantly, there is no single path for the preclinical development of a novel therapeutic and no proven strategy to ensure success in clinical translation. Rather, the conduct of a diverse array of robust preclinical studies reduces the risk of clinical failure by varying degrees depending upon the relevance of preclinical models and drug pharmacology to humans. A strong sense of urgency and high tolerance of failure are often required to achieve success in the development of novel treatment paradigms for complex human conditions.
F. R. Bahjat : R. Gesuete : M. P. Stenzel-Poore (*) Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, USA e-mail: [email protected]
Keywords Preconditioning . Stroke . Cardiovascular disease . Therapeutic . Animal models of stroke . Nonhuman primate . Mouse . MCAO . Occlusion . Toll-like receptors . Ischemia . Repercussion . Brain injury . Ischemic brain injury . Cerebral ischemia
Introduction The typical process for the evaluation of a novel preconditioning treatment includes in vitro cell-based assays and in vivo animal models of ischemia–reperfusion (I/R) injury or stroke. The breadth of studies recommended prior to clinical evaluation of novel agents depends upon a number of factors including: (1) the nature of the treatment, (2) the identity or location of the therapeutic target (e.g., receptor distribution and organ specificity), (3) the intended clinical indication (e.g., acute or chronic condition, comorbidities, age, sex, and species relevance), and finally,
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