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Biochemically modified messenger RNA encoding nucleases for in vivo gene correction of severe inherited lung diseases

Objective

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.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/rna
  • /medical and health sciences/medical biotechnology/cells technologies/stem cells
  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/medical biotechnology/genetic engineering/gene therapy

Call for proposal

ERC-2014-STG
See other projects for this call

Funding Scheme

ERC-STG - Starting Grant

Host institution

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Address
Geschwister-scholl-platz
72074 Tuebingen
Germany
Activity type
Higher or Secondary Education Establishments
EU contribution
€ 1 497 125

Beneficiaries (1)

EBERHARD KARLS UNIVERSITAET TUEBINGEN
Germany
EU contribution
€ 1 497 125
Address
Geschwister-scholl-platz
72074 Tuebingen
Activity type
Higher or Secondary Education Establishments