Modified messenger RNA as a tool for ex vivo and in vivo gene correction

• Applicant: Professor Michael Sebastian Daniel Kormann, Ph.D.
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2012 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 214845673

Although the use of messenger RNA (mRNA) for the treatment of inherited diseases would avoid genotoxicity, the clinical applications have thus far been limited to therapeutic cancer vaccination due to the strong immunogenicity and the limited stability of conventional mRNAs. In previous studies, we have found that a specific combination of nucleotide modifications abrogates mRNA interaction with several innate immune receptors, thus resulting in low immunogenicity and higher stability in mice. Using aerosolized modified mRNA coding for human Surfactant Protein B (SP-B), we achieved protection of SP-B deficient mice from respiratory failure and death, together with maintenance of normal lung function in the absence of lung inflammation in vivo. Based on those findings we will address the following issues in the proposed project: 1) optimizing delivery methods for mRNA-based gene correction ex vivo and in vivo; 2) implementing a gene manipulation of the SP-B locus in vivo using a combined approach of mRNA encoded specific Zinc Finger Nucleases (ZFNs) and adenoassociated viral (AAV) vector-delivered donor templates. Together, this would exploit modified mRNA as a versatile tool for both ex vivo and in vivo gene correction in multiple disease models.

• DFG Programme: Research Grants
• Participating Person: Dr. Lauren Elizabeth Mays