Description du projet
Thérapie génique pour les maladies pulmonaires
Le déficit en protéine B du surfactant (SP-B) est une maladie génétique rare qui provoque une détresse respiratoire sévère chez les nouveau-nés et peut conduire à une insuffisance respiratoire et à la mort. Les approches de thérapie génique visant à remplacer le gène muté se sont heurtées à des difficultés techniques. Le projet BREATHE, financé par l’UE, vise à améliorer les approches de thérapie génique pour le déficit en SP-B grâce à une méthode modifiée d’administration d’ARNm qui élimine le risque d’intégration génomique associé aux vecteurs à base d’ADN. Les chercheurs valideront leur approche sur des modèles murins de la maladie. En outre, ils appliqueront la même méthode à la thérapie de la mucoviscidose, une autre maladie génétique associée à la production de mucus épais et collant dans les poumons, à l’inflammation et aux infections récurrentes.
Objectif
Surfactant Protein B (SP-B) deficiency and Cystic Fibrosis (CF) are severe, fatal inherited diseases affecting the lungs of ten thousands of people, for which there is currently no available cure. Although gene therapy is a promising therapeutic approach, various technical problems, including numerous physical and immune-mediated barriers, have prevented successful application to date. My recent studies were the first to demonstrate the life-saving efficacy of repeated pulmonary delivery of chemically modified messenger RNA (mRNA) in a mouse model of congenital SP-B deficiency. By incorporating balanced amounts of modified nucleotides to mimic endogenous transcripts, I developed a safe and therapeutically efficient vehicle for lung transfection that eliminates the risk of genomic integration commonly associated with DNA-based vectors. I also assessed the delivery of mRNA-encoded site-specific nucleases to the lung to facilitate targeted gene correction of the underlying disease-causing mutations. In comprehensive studies, we show that a single application of nucleases encoded by nucleotide-modified RNA (nec-mRNA) can generate in vivo correction of terminally differentiated alveolar type II cells, which more than quadrupled the life span of SP-B deficient mice. Together with my working group, I aim to further develop this technology to enhance the efficiency and safety of nec-mRNA-mediated in vivo lung stem cell targeting, providing an ultimate cure by permanent correction. Specifically, we will test this approach in humanized mouse models of SP-B deficiency and CF. Developing and genetically engineering humanized models in vivo will be a critical step towards the safe translation of mRNA based nuclease technology to the clinic. With my competitive edge in lung-transfection technology and strong data, I feel that my group is uniquely suited to achieve these goals and to make a highly valuable contribution to the development of an efficient treatment.
Champ scientifique
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- engineering and technologynanotechnologynano-materials
Programme(s)
Thème(s)
Régime de financement
ERC-STG - Starting GrantInstitution d’accueil
72074 Tuebingen
Allemagne