Currently, spinal cord injuries have no effective treatments; physical rehabilitation can help patients regain some mobility, but for severe cases the results are extremely limited due to the failure of spinal neurons to regenerate naturally after injury. However, in a study published Sept. 20e in the open access journal PLOS Biologyresearchers led by Simone Di Giovanni of Imperial College London in the UK show that weekly treatments with an epigenetic activator can aid the regrowth of sensory and motor neurons in the spinal cord when given to mice 12 weeks after severe injury.
Building on their past success, researchers used a small molecule called TTK21 to activate genetic programming that induces axon regeneration in neurons. TTK21 alters the epigenetic state of genes by activating the CBP/p300 family of coactivator proteins. They tested the TTK21 treatment in a mouse model of severe spinal cord injury. The mice lived in an enriched environment that allowed them to be physically active, as is encouraged in human patients.
Treatment started 12 weeks after severe spinal cord injury and lasted 10 weeks. Researchers found several improvements after TTK21 treatment compared to control treatment. The most notable effect was that more axons grew in the spinal cord. They also found that the retraction of motor axons stopped above the point of injury and that the growth of the sensory axons increased. These changes were likely due to the observed increase in gene expression related to regeneration. The next step will be to amplify these effects even more and activate the regenerating axons to reconnect with the rest of the nervous system so that animals can regain their ability to move easily.
This work demonstrates that a drug called TTK21 administered systemically once a week after chronic spinal cord injury (SCI) in animals can promote neuronal regrowth and an increase in synapses needed for neuronal transmission. This is important because chronic spinal cord injury is a condition with no cure in which neuronal regrowth and repair fail. We are now investigating the combination of this drug with strategies that bridge the gap in the spinal cord, such as biomaterials, as possible ways to improve disability in SCI patients.”
Simone Di Giovanni, Imperial College London
Muller, F., et al. (2022) CBP/p300 activation promotes axon growth, germination and synaptic plasticity in chronic experimental spinal cord injury with severe disability. PLOS Biology. doi.org/10.1371/journal.pbio.3001310.