Epigenetic treatment in mice improves spinal cord regeneration after injury

New Imperial-led research shows that weekly epigenetic treatment in mice can support spinal cord regeneration after severe injury.

Currently, spinal cord injury does not have any effective treatments. Physical rehabilitation can help patients regain some mobility but, for severe cases, the outcomes are extremely limited by the failure of spinal neurons to regenerate naturally after injury. 

However, new research led by Professor Simone Di Giovanni and published in the journal PLOS Biology shows 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. 

Researchers used a small molecule called TTK21 to activate genetic programming that induces axon (nerve fibre) regeneration in neurons. TTK21 changes the epigenetic state of genes by activating the CBP/p300 family of co-activator proteins. The team tested TTK21 treatment in a mouse model of severe spinal cord injury. The mice lived in an enriched environment that gave them opportunities to be physically active, as is encouraged in human patients. 

Treatment began 12 weeks after severe spinal cord injury and lasted for 10 weeks. Researchers found several improvements after TTK21 treatment compared with control treatment. The most noticeable effect was more axon sprouting in the spinal cord. They also found that retraction of motor axons above the point of injury halted, and that sensory axon growth increased. These changes were likely due to the observed increase in gene expression related to regeneration. 

While the approach remains a long way from being trialled in human patients, the researchers say their early findings are encouraging. The next step will be to further enhance these effects and trigger the regenerating axons to reconnect to the rest of the nervous system so that animals can regain their ability to move with ease. 

Professor Di Giovanni commented: “This work shows that a drug called TTK21, when administered systemically once/week after a chronic spinal cord injury (SCI) in animals, can promote neuronal regrowth and an increase in synapses that are needed for neuronal transmission.

“This is important because chronic spinal cord injury is a condition without a cure where neuronal regrowth and repair fail. We are now exploring the combination of this drug with strategies that bridge the spinal cord gap such as biomaterials as possible avenues to improve disability in SCI patients.”

Müller F, De Virgiliis F, Kong G, Zhou L, Serger E, Chadwick J, et al. (2022) CBP/p300 activation promotes axon growth, sprouting, and synaptic plasticity in chronic experimental spinal cord injury with severe disability. PLoS Biol 20(9): e3001310 

Image credit: Franziska Mueller (CC-BY 4.0) 

Image description: Shown is an increased density of synapses (green) that contact motoneurons (purple) in the spinal cord of an injured animal after treatment with the small molecule TTK21-These are important for motor function.

This article has been adapted from a press release by PLOS Biology.