Project description

Patients with chronic obstructive pulmonary disease (COPD) suffer from chronic lung inflammation, tissue remodeling and persistent airflow limitation. Although corticosteroids and bonchodilatators can reduce the mortality risk, they still marginally improve lung function. There is an urgent need to 1) identify new therapeutic drugs, reducing inflammation and tissue remodeling, 2) design drug delivery strategies tailored to the COPD epithelium environment.
RNA treatments have demonstrated their potential for vaccination during the pandemic, but also for therapeutics using RNA interference to silence a dysfunctional protein or restore a damaged pathway. Several siRNA therapies have been approved in the recent years, opening the way for a new class of therapies for rare and uncurable diseases. Lipid nanoparticle have also revealed their potential to deliver such RNA, which are fragile molecules and cannot cross biological barriers. In this project, lipid nanoparticles will be improved by the use of aptamers as targeting ligands. Aptamers are single strand DNA or RNA which 3D conformation exhibit high affinity and selectivity for its biological target. Several aptamers have been used commercialized for diagnostics and therapy, but not yet for targeted drug delivery. In this project, we want to develop RNA therapy for COPD using lipid nanoparticles (LNP) targeted to the lung epithelium and assess these innovative therapies in relevant models. Our preliminary results demonstrate that lipid nanoparticles loaded with siRNA are internalized into primary cells of lung epithelium. To further improve our hypothesis, we intend to: i) develop a targeted LNP using aptamers for epithelial cells receptors, ii) screen several siRNA to demonstrate a functional benefit of siRNA therapy for COPD.

This project is in close collaboration between the ARNA research group “Targeted Aptamers, Medicines and Sensing”, led by Dr Jeanne Leblond Chain (www.tams.cnrs.fr), and CRCTB Team “Bronchial Remodeling” with Pr Isabelle Dupin (https://www.bronchialremodeling.com/).

The PhD student will 1/prepare lipid nanoparticles using microfluidic systems, functionalized with DNA aptamers and therapeutic siRNA (ARNA), 2/ develop robust characterization methods (fluorescence, DLS, microscopy) (ARNA) and 3/evaluate their transfection efficiency on 2D and 3D lung cellular models (microscopy, flow cytometry, Western Blot, ELISA, etc) (CRCTB).

Supervision and environment

The candidate will be supervised by Dr Jeanne Leblond Chain (INSERM Senior researcher, ARNA U1212) in collaboration with Isabelle Dupin (Professeur University of Bordeaux, CRCT). It will take place mainly in the Bordeaux Biologie Santé building in Carreire campus (146 avenue Leo Saignat, 33076 Bordeaux) and frequently in Hôpital Xavier Arnozan (CRCTB lab, which possess 2D and 3D models of primary lung cells).

Candidate profile

The PhD candidate should have a solid background in pharmaceutical sciences, nanomedicine and/or biochemistry. We are looking for a candidate motivated by the discovery of multi-disciplinary research, ranging from nucleic acid chemistry, lipid nanoparticles formulation but also cell and molecular biology, typical of the chemistry-biology interface. PharmD-PhD and MD-PhD students are encouraged to apply.