ProjektBREATHE – Biochemically modified messneger RNA encoding nucleases for in vivo gene correction of severe inherited…
Grunddaten
Akronym:
BREATHE
Titel:
Biochemically modified messneger RNA encoding nucleases for in vivo gene correction of severe inherited lung diseases
Laufzeit:
01.04.2015 bis 01.03.2020
Abstract / Kurz- beschreibung:
Surfactant Protein B (SP-B) deficiency and Cystic Fibrosis (CF) are severe, fatal inherited diseases affecting the lung 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 preliminary data, I feel that my group is uniquely suited to achieve these goals.
Beteiligte Mitarbeiter/innen
Leiter/innen
Medizinische Fakultät
Universität Tübingen
Universität Tübingen
Lokale Einrichtungen
Universität Tübingen
Geldgeber
Dirlewang, Bayern, Deutschland