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Local application of engineered insulin-like growth factor I mRNA demonstrates regenerative therapeutic potential in vivo .
- Source :
-
Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Oct 16; Vol. 34, pp. 102055. Date of Electronic Publication: 2023 Oct 16 (Print Publication: 2023). - Publication Year :
- 2023
-
Abstract
- Insulin-like growth factor I (IGF-I) is a growth-promoting anabolic hormone that fosters cell growth and tissue homeostasis. IGF-I deficiency is associated with several diseases, including growth disorders and neurological and musculoskeletal diseases due to impaired regeneration. Despite the vast regenerative potential of IGF-I, its unfavorable pharmacokinetic profile has prevented it from being used therapeutically. In this study, we resolved these challenges by the local administration of IGF-I mRNA, which ensures desirable homeostatic kinetics and non-systemic, local dose-dependent expression of IGF-I protein. Furthermore, IGF-I mRNA constructs were sequence engineered with heterologous signal peptides, which improved in vitro protein secretion (2- to 6-fold) and accelerated in vivo functional regeneration (16-fold) over endogenous IGF-I mRNA. The regenerative potential of engineered IGF-I mRNA was validated in a mouse myotoxic muscle injury and rabbit spinal disc herniation models. Engineered IGF-I mRNA had a half-life of 17-25 h in muscle tissue and showed dose-dependent expression of IGF-I over 2-3 days. Animal models confirm that locally administered IGF-I mRNA remained at the site of injection, contributing to the safety profile of mRNA-based treatment in regenerative medicine. In summary, we demonstrate that engineered IGF-I mRNA holds therapeutic potential with high clinical translatability in different diseases.<br />Competing Interests: Versameb AG is a privately held company focusing on discovering and developing innovative RNA-based drugs based in Basel, Switzerland. All authors affiliated with Versameb AG were employees during the course of this work and equity holders of Versameb.<br /> (© 2023 The Author(s).)
Details
- Language :
- English
- ISSN :
- 2162-2531
- Volume :
- 34
- Database :
- MEDLINE
- Journal :
- Molecular therapy. Nucleic acids
- Publication Type :
- Academic Journal
- Accession number :
- 37928443
- Full Text :
- https://doi.org/10.1016/j.omtn.2023.102055