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

Page et al., Journal of Neuroimmunology, 2023 asked whether knocking down a single inflammatory kinase in the injured spinal cord would improve how animals recover. MAPK-activated protein kinase 2, MK2, drives production of matrix metalloproteinases, inflammatory cytokines and nitric oxide, and mice that lack it entirely recover better after spinal cord injury. The open question was whether removing it after the injury, in the right place and at the right time, would do the same. AUM co-authored the work and supplied the reagents.

Eight AUMsilence sdASOs were designed against MK2 from reference sequence NM_008551.2 and screened in mouse bone marrow derived macrophages stimulated with bacterial lipopolysaccharide, alongside an AUM scramble control. Three of the eight cut MK2 messenger RNA by 70-80% and the other five changed nothing. The two strongest were carried into the animal experiment, where mice with a moderate contusion injury at the tenth thoracic level received two intrathecal injections of 10 mg/kg, the first immediately after injury and the second a day later. Only one of the two suppressed MK2 in the cord, halving it and holding that for at least 7 days. The sequence that had performed best in culture was not the one that worked in the animal.

The outcomes were mixed and the authors say so. Automated treadmill gait analysis at day 14 showed longer strides and less step angle variability in treated mice, while the open field locomotor score showed no difference between groups over 35 days. Lesion size at the epicentre was significantly smaller in treated mice at day 35. Other inflammatory messages, including tumour necrosis factor, interleukin 1b and CCL3, were unchanged, which the authors read as evidence that the knockdown hit its target and little else. They describe the functional benefit as mild and list what may have limited it, starting with a knockdown of only about half.