Development of a microRNA-155 inhibitor as a therapeutic for acute spinal cord injury Melanie Hermreck, Hillary Semus, David Hood, Aimee Jackson and Diana Escolar miRagen Therapeutics, 6200 Lookout Road, Boulder CO 80301
Objective: To develop a multi-pathway therapeutic approach to the treatment of acute spinal cord injury (SCI). Background:SCI often results in a permanent loss of motor, sensory and autonomic functions. Following the primary insult, secondary degeneration results from inflammation mediated by T lymphocytes, M1-type macrophages and microglia. miR-155 is a pro-inflammatory microRNA highly upregulated in activated immune cells driving the inflammatory response. In the CNS, miR-155 is expressed in activated microglia/macrophages, astrocytes and neurons, and genetic ablation of miR-155 improves repair and recovery in neuroinflammation. miRagen Therapeutics is developing a safe and effective treatment for traumatic SCI, selectively inhibiting inflammation and promoting axonal regeneration.
Design/Methods: miRagen Therapeutics, Inc. has evaluated kinetics and characteristics of immune cell infiltration, neuroaxonal degeneration and miR-155 expression in mice subjected to contusion SCI. Further, several oligonucleotide inhibitors of miR-155 (antimiR-155) were developed and the impact of antimiR-155 on locomotor and autonomic functions was assessed in vivo following multiple doses of the inhibitor by intravenous injection starting immediately after SCI.
Results:antimiR-155 treatment significantly increased hind-limb locomotor recovery and improved bladder function. Histological evaluation of the spinal cord showed significant reduction in neuroaxonal degeneration. Notably, effects on neuroaxonal protection were observed below the site of injury, which is typically the area of greatest impact on paralysis in individuals with SCI. Further, significant reduction in fibrosis in the soft tissue surrounding the site of injury was seen, which is known to aggravate axonal regeneration. Efficient uptake of antimiR-155 by cells in the spinal cord was demonstrated.
Conclusion:These data suggest that systemic administration of antimiR-155 following acute SCI has the potential to improve neuronal function and retain or restore autonomic function and mobility, addressing an area of high unmet need.
Credits: None available.
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