Projektbeschreibung
Gentherapie für Lungenerkrankungen
Ein Mangel des Surfactant-Proteins B (SP-B) ist eine seltene genetische Störung, die bei Neugeborenen zu schwerer Atemnot führt, die mit Lungenversagen und Tod enden kann. Bei dem Versuch, mit Gentherapieansätzen das mutierte Gen zu ersetzen, sind technische Schwierigkeiten aufgekommen. Über das EU-finanzierte Projekt BREATHE sollen Gentherapieansätze zur Behandlung des SP-B-Mangels vorangebracht werden. Dafür wird eine Methode zur Verabreichung modifizierter mRNA eingesetzt, die das Risiko der genomischen Integration umgeht, das bei DNS-basierten Vektoren besteht. Die Forschenden werden ihren Ansatz bei Mausmodellen der Krankheit prüfen. Zudem werden sie die gleiche Methode zur Behandlung von Mukoviszidose verwenden, einer weiteren genetischen Krankheit, bei der dicker, klebriger Schleim in den Lungen, Entzündungen und wiederkehrende Infektionen auftreten.
Ziel
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.
Wissenschaftliches Gebiet
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesmedical biotechnologycells technologiesstem cells
- natural sciencesbiological sciencesgeneticsmutation
- natural sciencesbiological sciencesgeneticsRNA
- engineering and technologynanotechnologynano-materials
Programm/Programme
Thema/Themen
Finanzierungsplan
ERC-STG - Starting GrantGastgebende Einrichtung
72074 Tuebingen
Deutschland