Vincent Sauzeau

Airway hyperresponsiveness (AHR) and pulmonary remodeling are hallmarks of asthma. The molecular mechanisms regulating airway smooth muscle cells (aSMC) contraction and proliferation involved in severe asthma are still largely unknown. Recently, we identified a new signaling pathway of regulation of intracellular Ca2+ by the small GTPase Rac1 that plays an essential role in aSMC bronchoconstriction (André et al. JACI 2018). In addition, we demonstrated that (i) Rac1 is activated in airways from mouse models of asthma, and (ii) the specific deletion of the Rac1 gene in smooth muscle cells prevents AHR and bronchial muscularization. Rac1 signaling thus appears as a new attractive therapeutic target in asthma. The challenge of this project is to translate our original findings and "proof-of-concept" from mice models of asthma to human disease and to evaluate the therapeutic potential of inhibiting the Rac1 signaling pathway in severe asthma patients.
Three research axes have been initiated to achieve these objectives :

  • Assessment of the expression and activity of Rac1 in airway smooth muscle of asthmatic patients
A cohort of severe and non-severe asthmatics is being set up, associated to a biocollection (blood, bronchoalveolar lavage cells, bronchial biopsies) and a large set of clinical data. Controls will be obtained from organ donors. Our objective is to determine if Rac1 expression and activity in aSMC are increased in bronchial biopsies from asthmatic patients compare to control samples and to test for correlation with the severity of the disease and the treatments.
 
  • Identification of Rac1 activators in asthma

Activation of Rac1 (corresponding to the switch from a GDP-bound state to a GTP-bound state) requires a guanine nucleotide exchange factor (Rac GEF) that catalyzes GDP to GTP exchange. The Rac GEF(s) responsible for the over-activity of Rac1 in asthma thus represent potentially valuable therapeutic targets. We will set up biochemical and proteomic approaches to identify Rac1 GEF activated in aSMC during asthma in allergic asthma experimental model (house dust mite-sensitized mice) and human biopsies, and assess their role in the development of the disease.

  • Discovery and development of new Rac1 inhibitors
After identification of specific Rac1 GEF(s) activated in aSMC during asthma, our aim will be to develop GEF/Rac1 interaction-specific small-molecule inhibitors. This project is based on our collaboration with computational and medicinal chemists. By in silico approaches, we will identify ligands targeting GEF/Rac1 interaction. The best candidates will be purchased and screened in vitro to evaluate their ability to inhibit Rac1 activity, their specificity and affinity, then in vivo in mouse models of asthma.

Publications & Patents

Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness.
André-Grégoire G, Dilasser F, Chesné J, Braza F, Magnan A, Loirand G, Sauzeau V.
J Allergy Clin Immunol. 2018 Sep;142(3):824-833.

[New protagonists in asthma pathophysiology].
Klein M, Dijoux E, Dilasser F, Hassoun D, Moui A, Loirand G, Colas L, Magnan A, Sauzeau V, Bouchaud G.
Presse Med. 2019 Mar;48(3 Pt 1):255-261. Review.

Patents

  1. "Methods and Pharmaceutical composition for inducing bronchodilatation". V. Sauzeau et al. (PCT/EP2014/062402)   
  2. "Inhibitors of rac1 and uses thereof for inducing bronchodilatation." V. Sauzeau et al. (EP17305662)

Funding

  • SATT Ouest valorisation
  • Région Pays de la Loire
  • Institut de Recherche en Santé Respiratoire
  • FRM
SATTOV

PDL
IRSR
FRM