Corticospinal tract (CST) regeneration is possible in patients with chronic spinal cord injury (SCI) by simple manipulation of the neurons, researchers at the Hong Kong University of Science and Technology (HKUST) recently discovered.

The finding will pave the way for potential new treatment options for chronic SCI, in which loss of mobility and sensation or paralysis often occurs and significantly impacts patients’ quality of life. Axonal growth of the injured neurons has been a major challenge in the field.

The HKUST researchers were able to regenerate axons of the central nervous system by deletion of the PTEN gene using an adult post-SCI mouse model. PTEN deletion in the adult cortex effectively reversed the downregulation of mammalian target of rapamycin (mTOR) that leads to loss of CST regrowth potential in SCI.

The study is not the first to attempt axonal regeneration by modulating the PTEN/mTOR pathway. Previous studies, however, only looked at PTEN knockdown in acute or subacute injury models. According to the HKUST researchers, this study is the first to show CST axonal regeneration in a chronic lesion.

“[PTEN deletion] not only promoted the sprouting of uninjured CST axons, but also enabled the regeneration of injured axons past the lesion in a mouse model of SCI, even when treatment was delayed up to 1 year after the original injury,” said lead researcher Professor Kai Liu. “CST plays an important role for functional recovery after SCI. The results considerably extend the window of opportunity for regenerating these severed axons.”

In the study, mice were treated at 1 month, 4 months, or 12 months post-injury. Compared to control mice not receiving treatment, a significant difference in the growth of CST axons was observed. Seven months after PTEN deletion initiated at 12 months post-injury, axonal regrowth was seen into the site of injury and up to 3 mm across the lesion site.

“It is interesting to find that chronically injured neurons retain the ability to reform tentative synaptic connections,” said Liu. “The functional outcome of the regenerated CST axons remains to be tested.”

Future work will need to take into consideration that PTEN is a tumour suppressor. The researchers hope to look into more rational and safe strategies targeting the intrinsic neuronal mechanisms of the mTOR pathway.

CST axons (in red) in control mice (top) and treated mice (bottom) after spinal cord crush at the lesion site (asterisk). Treatment initiated at 12 months post-injury.