Newsletter #6 – Modeling diversity in preclinical stroke

Taking clinical heterogeneity into account to increase the translational value of our preclinical models: the new STROK@LLIANCE research project

Early in 2019, we announced the launch of a collaborative research project aimed at improving the translational value of our innovative thrombo-embolic stroke models. In this project, clinical heterogeneity will be built into the models to evaluate the effects of co-morbidities, age and sex on outcomes and treatments. The team has already welcomed a PhD student, funded by CIFRE (Industrial Agreements for Research Training). We’re excited to be telling you about this new research project!

As both the leading cause of death and the top cause of severe disability¸ stroke is a major health problem worldwide. Sadly, few therapeutic options are available to the practitioner: only a small percentage of stroke patients can receive fibrinolysis or thrombectomy, mainly due to short therapeutic windows.

Despite more than two decades of intensive research in the field, all the treatments that were promising at the preclinical stage have failed in clinical studies, whatever the tested concept (improved fibrinolysis, therapeutic window extension, neuroprotection, or recovery improvement). This raises questions as to the relevance of available animal models (Fig. 1).

Figure 1: What have we learned from experimental animal stroke models? Similarities and discrepancies between preclinical and clinical studies

Although intraluminal MCAO models in rodents have led to numerous false positive results, probably due to significant limitations (see expert opinion #1), some academic laboratories have made a commitment to developing more translational models and establishing new gold standards. One such is the PhIND Laboratory in Caen (UMR U1237, academic partner to STROK@LLIANCE), which has fully validated an innovative model of thrombo-embolic stroke in mice that reproducibly mimics the essential features of human pathology and pharmacology (see newsletter #1).

This ischemic stroke model has been validated in healthy young male mice. While this configuration meets the strict need to reduce variability that is generally desired in preclinical pharmacology, it obscures the variability that can affect the efficacy of a drug during clinical trials. After all, isn’t stroke a complex heterogeneous pathology mainly affecting the elderly, often those suffering from comorbidities?

With this idea in mind we decided to explore this approach. Our main objective for this project is the production of a heterogeneous preclinical cohort of stroke-affected animals, including the main epidemiological and comorbid features in a proportion similar to those observed in the clinical situation. This is a matter of introducing variability and diversity into the preclinical studies.

After studying each factor independently, we will generate a cohort of stroke-affected animals inclusive of diversity. The first factors studied will be two major comorbidities: hypertension and diabetes (52% and 25% of patients are hypertensive or diabetic, respectively). Next, other factors such as age, sex or diet should be studied, possibly in different subsets of ischemic stroke etiologies that mimic cardioembolic vs. atherosclerotic origins (Fig. 2).

Figure 2: The STROK@LLIANCE research project: improving models by introducing diversity to preclinical models.

Firstly, the data collected will be useful in providing stroke pharmacological studies focused on a specific co-morbidity. Secondly, it will allow us to build up large-scale preclinical trials reproducing an aspect of clinical diversity. The point of such an innovative strategy is to better predict the effects of a drug candidate in clinic and, from the preclinical stage, to identify drug responder subgroups and anticipate the potential context of complications.

While ambitious, this project will (at the very least) provide numerous data and build our knowledge of the models. We at STROK@LLIANCE are therefore convinced that, in the current context of stroke pharmacological research, such an extensive piece of work is essential to bridging the gap between bench and bedside.

If you’re interested in our research projects and STROK@LLIANCE preclinical services, please feel free to get in touch!

Contact us

Newsletter #5


I) Strok@lliance’s scientific conference will be held every two years: see you in spring 2020!
II) European Stroke Action Plan 2018–2030: What about preclinical science?
VIDEO RELEASE – How does Strok@lliance commit to provide better preclinical services?

I) Strok@lliance’s scientific conference will be held every two years see you in spring 2020!

For the past two years, Strok@lliance has organised free annual scientific meetings focused on translational models and tools, bridging the gap between bench and bedside. Thanks to the 40-50 pharmaceutical industry attendees, all of whom are involved in drug development in the field of stroke, these events have proved a great success.

What happened at these meetings? Each year, neurologists, neuroradiologists, neurosurgeons and scientists have gathered at the prestigious Maison de la Chimie in Paris to spend a full day connecting preclinical and clinical practices, shedding light on the reality of human pathology and how it can be modelled in animals. In 2017, the day provided an overview of stroke aetiology, current acute management practices and animal modelling, and in 2018, the focus was on post-stroke deficit evaluation and rehabilitation, in both clinical and preclinical settings.

What’s next? Strok@lliance’s scientific conference will now be held every two years, to build the programme’s scientific quality. We look forward to seeing you in spring 2020 for our next event in Paris, where we expect to focus on translational imagery tools.

Please drop us a line if other topics are of interest to you… the more we share, the more our practice will improve!

II) European Stroke Action Plan 2018–2030: What about preclinical science?

Combatting stroke: pan-European team work

Stroke remains one of the leading causes of death and disability in Europe, and projections show that incidence of stroke is not set to fall in the next decade or beyond. According to the European Stroke Organisation (ESO): “There is compelling evidence that stroke is highly preventable, treatable and manageable. However, this requires the joint actions of governments, support organisations, healthcare professionals, clinical and preclinical researchers and the pharmaceutical and device industries”.

This is why ESO has published a European Stroke Action Plan for 2018 to 2030, following the conclusions of pan-European working groups in seven domains of interest, including primary prevention, the organisation of stroke services and rehabilitation. Patient organisations are represented in each domain.

In addition, a working group that includes our academic partner, Pr. Denis Vivien, has focused on translational stroke research.

What about preclinical stroke research?


The development of more relevant experimental models that mirror the complexity of human diseases is a key challenge in preclinical research for the coming years.

Regarding reperfusion studies, models allowing different clot compositions and locations to be mimicked should be used to improve acute therapeutic strategies in a personalized medical approach. The concept of neuroprotection has evolved to become more holistic, since protection is required for functional units made up of neurons, glial cells, pericytes, macrophages and the vasculature. In particular, models of white matter lesion and small vessel disease, as well as new imaging tools, are required for the study of vascular integrity, haemodynamic responses and blood–brain barrier function.

Regarding targets, inflammatory and immune responses as well as oxidative or nitrosative stress at reperfusion are promising. Regarding haemorrhagic stroke, new molecular processes including inflammation have been identified, yet translational models of aneurysm are not in common use and still need to be improved. Overall, the diversity observed in clinical practice is not being satisfactorily mimicked, because the introduction of comorbidities and reasonable variability (genetics, age, sex, stroke intensity, etc.) in preclinical models has yet to be implemented, despite STAIR’s recommendation of 20 years ago.

“Recent research provides hope of developing new and effective treatments for stroke. However, the translation from basic to clinical research has failed over recent decades, underlining the need for innovative methodological strategies. Networking between laboratory scientists and clinicians, better experimental designs and more relevant experimental models are required to improve our science.”

Pr. D. Vivien

On the methodological side, preclinical confirmatory studies, designed entirely separately from exploratory studies, should be performed as an intermediate translational step. Here, the goal is to bring preclinical practice closer to clinical study quality and methodology (e.g. rigorous methodology, transparency, availability of the data, etc.).

The link to the full ESO publication: “Action Plan for Stroke in Europe 2018–2030” is here: 


III) How does Strok@lliance commit to provide better preclinical services?

Thanks to a unique academic/private partnership, Strok@lliance is able to provide state-of-the-art preclinical services, anticipating future needs and directions in the field.

Strok@lliance therefore offers original translational rodent stroke models and imaging tools issuing from Pr. Vivien’s research team, to meet the need for more translational studies. With more than 25 years of expertise behind it, ETAP-Lab guarantees that studies are performed in compliance with the very highest quality standards.

Strok@lliance is also proud to announce the spring 2019 launch of a PhD thesis project (co-financed by both partners) to assess the impact of comorbidities and introduce variability in a translational model of thrombotic stroke in mice.

To find out more about the future of translational stroke research, please watch Pr. Vivien’s presentation from the 2018 Strok@lliance meeting at the Maison de la Chimie.

Link to the video

Link to the Newsletter

Back to the Strok@lliance Second Annual Meeting

Post-stroke deficits and recovery from bench to patient’s bed

This year again, Strok@lliance aimed at bridging the gap between laboratory and clinical practices. The event occured at the Maison de la Chimie, the 5th of June 2018, and gathered nearly 40 participants, mainly coming from the industry.

During the conferences, key opinion leaders in the field of stroke enlightened the reality of post-stroke deficit evaluation and rehabilitation in both the setting of clinical trials and medical cares. Among them, Pr Serge Timsit talked about stroke modelling in preclinic: bridging the gap from bedside to bench. Whereas, Pr Alain Yelnik shared his knowledge about motricity stimulation strategy for stroke recovery in clinic.

It was also the opportunity for Strok@lliance’s team to share some innovative behavioral tests and research strategies in rodents, supporting the major impact of preclinical research on the design of clinical studies.

Take a look at the event videos and see you next year for the Strok@lliance 3rd annual meeting !

2nd Strok@lliance annual meeting was a success!

This year again, Strok@lliance aimed at bridging the gap between laboratory and clinical practices. Therefore, the second annual meeting of Strok@lliance took place at La Maison de la Chimie in Paris on June 5, 2018.

During the conference, key opinion leaders in the field of stroke enlightened the reality of post-stroke deficit evaluation and rehabilitation in both the setting of clinical trials and medical cares. The event gathered nearly 40 participants, coming from both the public and the industry. It was also the opportunity for Strok@lliance’s team to share some innovative behavioral tests and research strategies in rodents, supporting the major impact of preclinical research on the design of clinical studies.

Follow the video release of the conferences during next weeks on strok@lliance website (sucscribe via our contact form).

Thanks again to all the attendees, see you next year for the Strok@lliance 3rd annual meeting.

The Strok@lliance’s Team

2nd Strok@lliance Annual Meeting

June 5th, 2018 – 10:00 AM – 4:30 PM
28 Rue Saint-Dominique, 75007 Paris

Post-stroke deficits and recovery from bench to patient’s bed
Any translational end-points to come?


For decades, preclinical stroke studies have failed to predict neuroprotective drug efficacy in clinic. Many reasons have been pointed out, among them the difficulty to induce reproducible and long-lasting functional outcomes in preclinical studies. It is a critical issue considering that clinical interventions focus on patient functional deficits and recovery.

It is time to start rethinking post-stroke behavioral testing in preclinical studies. This point will be the subject of presentations and discussions during our annual meeting on June 5th in Paris. This year again, Strok@lliance’s meeting will aims at bridging the gap between laboratory and clinical practices.
For one day, neurologists, clinicians and researchers will enlighten the reality of post-stroke deficit evaluation and rehabilitation in both the setting of clinical trials and medical cares. Some innovative behavioral tests and research strategies in rodents will be presented before a debate where clinician will share their vision of the value and needs in current preclinical behavioral studies.

Come to share your points of view and listen to the conferences on June 5th 2018!

Free Registration!


Download the full program

Focus on an innovative model of thromboembolic stroke reproducing the clinical situation

Recombinant tissue-type plasminogen activator (rt-PA) is the only approved drug treatment at the acute phase of ischemic stroke in the US and Europe. However, rt-PA has a short therapeutic window (4.5h after stroke onset), mainly because of the increased risk of hemorrhagic transformation from this time. Thus, only a few percentage of stroke patients will benefit from rt-PA-induced thrombolysis.

These last two decades, despite the efforts made to improve fibrinolysis or to develop neuroprotective drugs, all of them failed at the clinical stage. It is well admitted that experimental models of stroke are either too severe, not enough reproducible, or do not sufficiently mimic pathophysiology of the Human disease for a correct evaluation of drugs efficacy including neuroprotectants, thrombolytics alone or in combination.

In order to solve this problem, ESRP scientists developed a new translational model of thromboembolic stroke in mice, which overcomes several of these pitfalls. This model is now available for pharmacological studies with Strok@lliance.

In situ thromboembolic  stroke is induced by the injection of purified thrombin in the Middle Cerebral Artery (MCA) at M1/M2 bifurcation, modelling a distal thrombosis eligible for thrombolytic treatments in humans. It results in reproducible ischemic lesions in the somatosensory cortex (≈20 mm3 ; Fig. 1). Moreover, it produces a significant strength deficit of the contralateral paws, lasting up to 14 days after stroke onset thus allowing functional recovery studies.

Figure 1. A. Thrombin injection in the MCA at M1/M2 bifurcation; B. Cerebral blood flow reduction in the ischemic hemisphere at stroke onset (laser speckle imaging); C. Representative lesion at 24h after stroke onset in saline-treated mice (T2* MRI).

Due to its fibrin-rich content, the produced clot is sensitive to rt-PA induced thrombolysis. A retrospective data analysis from 26 preclinical studies performed with this model in 9 independent academic laboratories allowed to estimate the therapeutic windows of rt-PA on cerebral lesion volume. When started early after stroke onset, i.e. less than 40 min post-stroke, rt-PA treatment induces a reproducible reduction of the cerebral injury; treatment starting later than 90 min had no or deleterious effects. This study also confirmed the intra- and inter-laboratory reproducibility of this model (Fig. 2).

Thus, this model reproduces key features of human pathophysiology and pharmacology, while overcoming several pitfalls of classical models.

Figure 2. Effects of rt-PA i.v. perfused at 10 mg/kg when administered 30 min or 4 hours after stroke onset on: A. infarct volume and B. Brain oedema. Data are expressed as mean ± SEM. *** P < 0.001 versus saline.

Orset C. et al. (2007) Mouse model of in situ thromboembolic stroke and reperfusion. Stroke 38:2771-8.

Macrez R. et al. (2011) Antibodies preventing the interaction of tissue-type plasminogen activator with N-methyl-D-aspartate receptors reduce stroke damages and extend the therapeutic window of thrombolysis. Stroke 42:2315-22.

El Amki M. et al. (2012) Experimental modeling of recombinant tissue plasminogen activator effects after ischemic stroke. Experimental neurology 238:138-44.

“Composed of highly skilled specialists, Strok@lliance is now able to manage projects for the pharmaceutical industry, ensuring that both expertise and creativity are brought into play in providing high-level animal studies in a quality-controlled environment. By taking full advantage of the CYCERON facilities, Strok@lliance accesses state-of-the-art technology and offers fine-tuned behavioral studies.”

N. Violle, Etap-Lab CEO, Strok@lliance Executive Partner