Epigenetic treatment in mice improves spinal cord regeneration after injury

There are currently no effective treatments for spinal cord injuries; physical rehabilitation can help patients regain some mobility, but in severe cases, results are extremely limited by the failure of spinal cord neurons to regenerate naturally after injury. In a study published on 20^th 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 support the regrowth of sensory and motor neurons in the spinal cord when given to mice 12 weeks after a severe injury.

Building on their previous success, the researchers used a small molecule called TTK21 to activate the genetic programming that induces axon regeneration in neurons. TTK21 alters the epigenetic state of genes by activating the CBP/p300 family of co-activator proteins. They tested TTK21 treatment in a mouse model of severe spinal cord injury. The mice lived in an enriched environment that gave them the opportunity to be physically active, as encouraged in human patients.

Treatment began 12 weeks after a severe spinal cord injury and lasted 10 weeks. The researchers found several improvements after TTK21 treatment compared to the control treatment. The most striking effect was that more axons sprout in the spinal cord. They also found that motor axon retraction stopped above the point of injury and that sensory axon growth increased. These changes were likely due to the observed increase in gene expression associated with regeneration. The next step will be to amplify these effects even further and stimulate the regenerating axons to reconnect with the rest of the nervous system so the animals can regain their mobility.

Di Giovanni adds: “This work shows that a drug called TTK21, given 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 will. This is important because chronic spinal cord injury is an uncurable condition in which regrowth and repair of neurons fail. We are now investigating combining this drug with strategies that close the gap in the spinal cord, such as B. Biomaterials, as possible ways to improve disability in SCI patients.”

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Please use this URL in your reporting to enable access to the freely available paper PLOS biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001310

Citation: Müller F, De Virgiliis F, Kong G, Zhou L, Serger E, Chadwick J, et al. (2022) CBP/p300 activation promotes axon outgrowth, sprouting, and synaptic plasticity in chronic experimental spinal cord injury with severe disability. PLoS Biol 20(9): e3001310. https://doi.org/10.1371/journal.pbio.3001310

author countries: United Kingdom, India

Financing: ISRT translational award-P90397 to SDG Marina Romoli Onlus-P82836 to SDG Rosetrees Trust-P72986 to SDG Brain Research Trust-P73576 to SDG .