Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

 This is so simple, you have NO LEADERSHIP AND NO STRATEGY. You are allowing researchers to willy nilly do whatever they think can get funded.

Translational Block in Stroke: A Constructive and “Out-of-the-Box” Reappraisal

Athanasios Lourbopoulos^1,2,3*, Iordanis Mourouzis¹, Christodoulos Xinaris^4,5, Nefeli Zerva¹, Konstantinos Filippakis¹, Angelos Pavlopoulos¹ and Constantinos Pantos¹

• ¹Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
• ²Department of Neurointensive Care Unit, Schoen Klinik Bad Aibling, Bad Aibling, Germany
• ³Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig Maximilian University, Munich, Germany
• ⁴IRCCS – Istituto di Ricerche Farmacologiche ‘Mario Negri’, Centro Anna Maria Astori, Bergamo, Italy
• ⁵University of Nicosia Medical School, Nicosia, Cyprus

Why can we still not translate preclinical research to clinical treatments for acute strokes? Despite > 1000 successful preclinical studies, drugs, and concepts for acute stroke, only two have reached clinical translation. This is the translational block. Yet, we continue to routinely model strokes using almost the same concepts we have used for over 30 years. Methodological improvements and criteria from the last decade have shed some light but have not solved the problem. In this conceptual analysis, we review the current status and reappraise it by thinking “out-of-the-box” and over the edges. As such, we query why other scientific fields have also faced the same translational failures, to find common denominators. In parallel, we query how migraine, multiple sclerosis, and hypothermia in hypoxic encephalopathy have achieved significant translation successes. Should we view ischemic stroke as a “chronic, relapsing, vascular” disease, then secondary prevention strategies are also a successful translation. Finally, based on the lessons learned, we propose how stroke should be modeled, and how preclinical and clinical scientists, editors, grant reviewers, and industry should reconsider their routine way of conducting research. Translational success for stroke treatments may eventually require a bold change with solutions that are outside of the box.

Introduction – The Problem of Translational Failure in Stroke

Stroke remains the third leading cause of death in industrialized countries (Dirnagl et al., 1999). The literature is saturated by >1000 effective preclinical studies in acute stroke research (O’Collins et al., 2006), yet almost none are successfully transferred to the acute clinical routine. This is the well-known translational failure or block in stroke research (Endres et al., 2008).

The “basket” of stroke translational failure so far includes neuroprotective agents (O’Collins et al., 2006), stem cells (Borlongan, 2019), or even novel immunological treatments (Elkins et al., 2017), despite rigorous or/and large preclinical effect sizes. Yet we keep on modeling acute stroke and experimenting using, in most cases, the same concepts based on widely cited models. Is this the right way to continue and progress or do we simply need to critically reassess how we model ischaemic stroke?

The fact is that many pathophysiological principles of stroke were actually discovered in translation (Dirnagl and Endres, 2014). Failed clinical trials for acute stroke were probably based on rather weak preclinical evidence or inappropriate models (Drieu et al., 2020). If we consider stroke a “chronic, relapsing” disease, with multiple repeating small or large ischemic insults, then secondary prevention counts for several successes (Kernan et al., 2014). On the other hand, the differences between preclinical rodent modeling and clinical routine practice in human acute stroke are significant (Corbett et al., 2015). Nevertheless, preclinical research has several translational success stories, such as the case of experimental autoimmune encephalomyelitis (EAE) – multiple sclerosis (MS), migraine, and hypothermia in hypoxic-ischaemic encephalopathy (HIE). In addition, existing recommendation papers and consortiums [e.g., ARRIVE (Kilkenny et al., 2010), STAIR (Corbett et al., 2017), STEPS (Savitz et al., 2011)] have repeatedly proposed pathways to success. However, either few groups worldwide are implementing these guidelines or we are still missing some of the factors that are involved in failure.

Hence, we provide here a critical, interdisciplinary, and revisionary overview of stroke translational failure, taking into consideration lessons from “success stories” and “failed concepts” in neuro-research. We argue that translational failure is also the rule in ischaemia of other organs, such as myocardial infarction. Collectively, we believe that translational failure probably lies in fundamental components and “false” choices in the laboratory and clinical research. If we want to succeed, we need to improve not only the current technical hurdles in contemporary neurosciences, but also the way we put our question into perspective (Kola and Landis, 2004; Duda et al., 2014; Garner, 2014; Alteri and Guizzaro, 2018).

“We can’t solve problems by using the same kind of thinking we used when we created them.”

Albert Einstein (1879–1955)

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