Local application of engineered insulin-like growth factor I mRNA demonstrates regenerative therapeutic potential in vivo

Justin S Antony; Pascale Birrer; Claudia Bohnert; Sina Zimmerli; Petra Hillmann; Hervé Schaffhauser; Christine Hoeflich; Andreas Hoeflich; Ramzi Khairallah; Andreas T Satoh; Isabelle Kappeler; Isabel Ferreira; Klaas P Zuideveld; Friedrich Metzger

doi:10.1016/j.omtn.2023.102055

Local application of engineered insulin-like growth factor I mRNA demonstrates regenerative therapeutic potential in vivo

Mol Ther Nucleic Acids. 2023 Oct 16:34:102055. doi: 10.1016/j.omtn.2023.102055. eCollection 2023 Dec 12.

Affiliations

¹ Versameb AG, Technology Park, 4057 Basel, Switzerland.
² Ligandis, 18276 Gülzow-Prüzen, Germany.
³ Myologica LLC, Baltimore, MD 21212, USA.

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.

Keywords: IGF-I; MT: RNA/DNA Editing; disc herniation; mRNA therapy; muscle injury; regeneration.