Self-delivering mRNA inhibitors of MK2 improve outcomes after spinal cord injury

Functional recovery and tissue damage after spinal cord injury (SCI) are influenced by secondary damage mechanisms, including inflammation. The inflammatory response after SCI relies on a variety of cell types with both protective and cytotoxic functions. The macrophage derived MAPK-activated protein kinase 2 has been described as a critical regulator of inflammation with detrimental function after SCI. Targeted modification of inflammatory effector molecules after SCI faces challenges of optimal timing, dosage and location of administration. Modified RNA inhibitors, FANA antisense oligonucleotides, are promising inhibitors due to their stability, local penetration of cells and high efficacy in targeted suppression. Here, we describe the use of anti- MAPK-activated protein kinase 2 FANA antisense oligonucleotides in a mouse model of contusional SCI. The most efficient inhibitor was selected with in vitro and in vivo techniques and then applied via intrathecal injections after SCI. This treatment resulted in improved gait applying DigiGait assessments and tissue preservation, indicating the usefulness of the target and inhibition approach. •MK2 is a critical regulator of inflammation with detrimental effect after SCI.•FANA ASO molecules are promising translational RNA inhibitors.•MK2 inhibition resulted in mild improvement of functional recovery after SCI.•MK2 inhibition led to better tissue preservation after SCI.