Descripción del proyecto
Terapia génica para enfermedades pulmonares
La deficiencia de proteína tensioactiva B (SP-B, por sus siglas en inglés) es un trastorno genético poco frecuente que provoca dificultades respiratorias graves en recién nacidos y puede provocar tanto insuficiencia respiratoria como el fallecimiento. Los métodos de terapia génica para sustituir el gen mutado se han enfrentado a dificultades técnicas. El equipo del proyecto BREATHE, financiado con fondos europeos, pretende mejorar los métodos de terapia génica contra la deficiencia de SP-B mediante un método modificado de administración de ARNm que elimina el riesgo de integración genómica asociado a los vectores basados en ADN. Los investigadores validarán su método en modelos murinos de la enfermedad. Además, aplicarán el mismo método para el tratamiento de la fibrosis quística, otra enfermedad genética asociada a la producción de mucosidad espesa y pegajosa en los pulmones, inflamación e infecciones recurrentes.
Objetivo
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.
Ámbito científico
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- engineering and technologynanotechnologynano-materials
Programa(s)
Régimen de financiación
ERC-STG - Starting GrantInstitución de acogida
72074 Tuebingen
Alemania