Restoration of Motor Function through Delayed Intraspinal Delivery of Human IL-10-Encoding Nucleoside-Modified mRNA after Spinal Cord Injury

László Gál; Tamás Bellák; Annamária Marton; Zoltán Fekécs; Drew Weissman; Dénes Török; Rachana Biju; Csaba Vizler; Rebeka Kristóf; Mitchell B Beattie; Paulo J C Lin; Norbert Pardi; Antal Nógrádi; Krisztián Pajer

doi:10.34133/research.0056

Restoration of Motor Function through Delayed Intraspinal Delivery of Human IL-10-Encoding Nucleoside-Modified mRNA after Spinal Cord Injury

Research (Wash D C). 2023:6:0056. doi: 10.34133/research.0056. Epub 2023 Mar 9.

Authors

Affiliations

¹ Department of Anatomy, Histology and Embryology, Albert Szent-Györgyi Medical School, University of Szeged, Szeged, Hungary.
² National Biotechnology Laboratory, Institute of Genetics, Biological Research Centre, Szeged, Hungary.
³ Institute of Biochemistry, Biological Research Centre, Szeged, Hungary.
⁴ Department of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
⁵ Acuitas Therapeutics, Vancouver, BC, V6T 1Z3, Canada.

Abstract

Efficient in vivo delivery of anti-inflammatory proteins to modulate the microenvironment of an injured spinal cord and promote neuroprotection and functional recovery is a great challenge. Nucleoside-modified messenger RNA (mRNA) has become a promising new modality that can be utilized for the safe and efficient delivery of therapeutic proteins. Here, we used lipid nanoparticle (LNP)-encapsulated human interleukin-10 (hIL-10)-encoding nucleoside-modified mRNA to induce neuroprotection and functional recovery following rat spinal cord contusion injury. Intralesional administration of hIL-10 mRNA-LNP to rats led to a remarkable reduction of the microglia/macrophage reaction in the injured spinal segment and induced significant functional recovery compared to controls. Furthermore, hIL-10 mRNA treatment induced increased expression in tissue inhibitor of matrix metalloproteinase 1 and ciliary neurotrophic factor levels in the affected spinal segment indicating a time-delayed secondary effect of IL-10 5 d after injection. Our results suggest that treatment with nucleoside-modified mRNAs encoding neuroprotective factors is an effective strategy for spinal cord injury repair.