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Page 2 of 8 Lee et al. Vessel Plus 2021;5:8 I http://dx.doi.org/10.20517/2574-1209.2020.72

positive impact of reperfusion-based therapies, acute ischemic stroke (AIS) patients continue to suffer
substantial disability. Among patients treated with mechanical thrombectomy, 50% are functionally
[3-5]
dependent and 75% are disabled at 90 days . Thus, there is critical need to continue to develop novel
therapies that can either enhance reperfusion or improve outcomes regardless of reperfusion. Among
these additional targets is neuroprotection - the strategy of interfering with the ischemic cascades by
blocking cellular and molecular pathways leading to neuronal cell death. Targets of neuroprotection
include excitotoxicity - the pathological excitation of neurons due to the massive release of the excitatory
neurotransmitter glutamate-cellular influx of calcium, generation of free radicals, and inflammatory
cascades [6,7] . However, failure of translation from experimental models to successful human trials
has virtually halted the drug development pipeline for neuroprotection. As a result, investment by
pharmaceutical companies in this market has been limited. However, in this new era of reperfusion
therapy, neuroprotection is being actively reconsidered, with the premise that earlier trials failed because
[8]
neuroprotectants were unable to reach ischemic tissue in adequate concentrations .
FAILURE OF FORWARD TRANSLATION
Despite five decades of translational research on ischemic brain injury mechanisms, there are no widely
accepted neuroprotective drugs for the treatment of AIS. It has been estimated that over a thousand drug
[9]
targets have been identified from cellular or animal models . Of these, less than 100 have been tested
[9]
in human clinical stroke trials , and virtually all trials have been negative. These poor odds identify the
translation from preclinical studies to clinical trials as a bottleneck in identifying drug targets relevant to
human disease [Figure 1A].

These trial failures led to a period of deep introspection in the field, with many questioning the validity of
preclinical animal models for discovering novel drug targets for translation to human clinical trials [10-12] .
The discussion also stimulated a re-examination of the rigor of early stroke trials, which often did
not confirm target engagement or adhere to relevant therapeutic time windows [13-15] . To enhance the
translational potential of new experimental therapies, the Stroke Therapy Academic Industry Roundtable
(STAIR) published guidelines in 1999 to develop rigorous criteria for preclinical studies in animal models.
Among the recommendations were pretrial sample size calculations, randomization, blinded allocation,
[16]
and endpoint assessments, the inclusion of aged animals with comorbid conditions . However, preclinical
studies that adhered to STAIR criteria still failed in subsequent clinical trials [17,18] . Despite updated STAIR
[19]
criteria , we have yet to have a positive clinical trial for neuroprotection.

It is clear that the traditional approach of forward translation - starting at the bench with the identification
of potential drug targets and translating to clinical trials - is costly and inefficient. Are there alternative or
complementary approaches towards validating drug targets in humans?

REVERSE TRANSLATION - GWAS
Over the last decade, genome-wide-association studies (GWAS) have identified thousands of genetic
variants that are associated with human traits and diseases. GWAS takes advantage of natural variation
in the human genome to identify genetic markers that associate with specific traits or diseases. Unlike
candidate gene approaches, which examine the association between a given trait and select candidate genes,
GWAS examines associations between the trait and genetic markers across the entire genome, creating a
large-scale unbiased approach. Over 3,000 human GWAS have investigated more than 1,800 diseases and
[20]
traits yielding thousands of genetic associations . Examples of diseases that have led to the discovery of
genes and pathways involved in pathogenesis include age-related macular degeneration , inflammatory
[21]
[25]
[26]
[22]
[23]
[24]
bowel disease , cardiovascular disease , obesity , schizophrenia , and Alzheimer disease . While
these genetic associations are often weak, accounting for only a small amount of the risk for the disease,