Assistant Professor in Dr Cécile Duplàa‘s team, in the Inserm U1034 unit headed by Prof. Thierry Couffinhal, Claire Peghaire has been awarded the SPARK Bordeaux 2024 program prize from among 8 winners for her project using drug repurposing strategy to treat small cerebral vessel disease (cSVD). Interview.
What’s your background?
I have a doctorate in pharmacy and a doctorate in science specializing in Cell Biology, Physiology and Pathology (2014) from the University of Bordeaux.
My thesis work (Inserm U1034 Biology of Cardiovascular Diseases, Pessac, France) focused on studying the role of the Frizzled7 receptor in physiological and pathological angiogenesis via the regulation of the Wnt/β-catenin pathway.
During my postdoctorate at the National Heart and Lung Institute (Imperial College London, London, UK) with Prof. Anna Randi (2015-2020), I developed projects on the regulation of hemostasis and vascular homeostasis by the endothelial transcription factor ERG and its involvement in microvascular pathologies.
Appointed Assistant Professor in 2021 at the University of Bordeaux and Inserm U1034, my current research aims to:
- study the contribution of endothelial dysfunction and vascular lesions to the pathogenesis of cerebrovascular disease and cognitive impairment,
- identify new molecular players and therapeutic targets involved in cSVD, using complementary and innovative in vivo and in vitro approaches.
What is drug repositioning to treat cSVD?
Drug repositioning involves the use of drugs already on the market to treat a different disease from the original indication. Despite technological advances, developing a new drug is a long and costly process.
Fifteen years of research and development are generally required before a new drug is brought to market.
The drug repositioning strategy saves time and money, as the drug’s safety has already been proven in clinical trials.
In the context of cSVD, our aim is to test, in our innovative preclinical model of this pathology, the effect of antioxidant molecules already used in the treatment of other neurodegenerative diseases.
Why are you interested in this subject?
cSVD is a chronic and progressive vascular pathology predisposing to vascular dementia and Alzheimer’s disease. It is a major cause of stroke and key contributor to cognitive decline. It is associated with environmental factors (age, hypertension, etc.), but its precise cause and etiology remain unknown.
While it is possible to limit certain risk factors, there is no curative treatment. With ageing population, cSVD represents a growing public health challenge.
A better understanding of the disease development process (its pathogenesis) is therefore essential to develop therapeutic strategies aimed at improving cognitive function in patients.
Using large-scale human genomics data generated by Prof. Stéphanie Debette as part of the RHU-SHIVA consortium, we have discovered a new biological target of cSVD, TRIM47, which is present in the blood vessels of the brain and more specifically in endothelial cells lining these blood vessels.
We recently demonstrated that TRIM47 protects endothelial cells from oxidative stress via activation of the antioxidant signalling pathway controlled by the transcription factor NRF2. Our mouse model, in which we have removed the Trim47 protein, mimics the key symptoms of human disease and demonstrates that the TRIM47/NRF2 system is essential for maintaining good brain health (international patent: WO/2024/047248 and preprint article on bioRxiv).
What are the expected results?
In France, it is estimated that over 5 million people, aged 65 and over, suffer from a cSVD (40 million in Europe) and could benefit from prevention strategies to avoid or delay strokes, vascular dementia and cerebral aging.
The aim of our project is to test a strategy for repositioning antioxidant drugs that are activators of the protective NRF2 pathway in our mouse model of cSVD, in order to assess their ability to prevent vascular and neuronal dysfunction, as well as cognitive impairment in animals.
The use of cutting-edge brain imaging technologies and behavioral tests in mice to study symptoms present in humans will give us a better understanding of the mechanisms involved, and validate the relevance of targeting this TRIM47/NRF2 pathway to combat this disease.
We hope that the results of this translational study will enable us to set up trials in humans, in order to transpose our research into the clinic.
What does the SPARK Bordeaux program offer you?
The SPARK Bordeaux program offers 2 years of tailored mentoring. The aim is to increase the chances of transforming our lab research results into real clinical solutions for patients.
As a project leader, this program will enable me to meet local and international industry experts, and gain valuable advice for the development of our project. Indeed, the aim of this drug repositioning project is to provide robust preclinical results that will enable us to potentially launch a clinical trial with industrial partners.
SPARK Bordeaux gives us the opportunity to receive invaluable support at key stages of our project, and to learn about entrepreneurship, the creation of a start-up and the prerequisites for setting up and developing a clinical trial with an already known molecule.
More broadly, this program is a fabulous opportunity to capitalize on the results of our research, which will be carried out at Inserm U1034, as part of the VBHI.
Further information:
- Scientific article in preprint: Cerebral Small Vessel Disease genetic determinant TRIM47 controls brain homeostasis via the NRF2 antioxidant system, Cécile Duplàa, Valentin Delobel, Romain Boulestreau, Sébastien Rubin, Juliette Vaurs, Béatrice Jaspard-Vinassa, Muriel Busson, Cloé Combrouze, Carole Proust, Jean- Luc Morel, Bruno Bontempi, Aniket Mishra, Stéphanie Debette, Thierry Couffinhal, Claire Peghaire
bioRxiv 2024.10.08.616723; doi: https://doi.org/10.1101/2024.10.08.616723 - SPARK Bordeaux program: https://spark.u-bordeaux.fr/en/
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