PTEN Deletion Post SCI Regeneration and Recovery

Over the last few years we have written several times about a nifty genetic manipulation that reboots key nerves in the spinal cord to regenerate in a big way. Starting back in 2008, Zhigang He, at Harvard, got damaged optic nerves going again by deleting PTEN, a tumor suppressor gene that cancer researchers had come across back in the 1990s; this enzyme acts as a sort of brake when axons attempt to regenerate after injury.

In the world of cancer, of course, the idea is to keep the growth brake on; in spinal cord repair, it's just the opposite. Anyway, in later experiments, when PTEN was removed, the corticospinal tract (CST) regenerated in lab animals - important because the CST comprises crucial wiring for arm and hand function.

The most recent research, from Camilla Da anilov and Oswald Steward at the Reeve-Irvine Research Center at the University of California, Irvine, takes a big step toward clinical relevance. In all previous experiments, animals used in the tests had PTEN deleted before they were spinal cord injured. This time, they took the PTEN brakes off after animals had been paralyzed.

The paper, out in the journal Experimental Neurology, is titled "Conditional genetic deletion of PTEN after a spinal cord injury enhances regenerative growth of CST axons and motor function recovery in mice." From the abstract: Previous studies indicate that conditional genetic deletion of phosphatase and tensin homolog (PTEN) in neonatal mice enhances the ability ofaxons to regenerate following spinal cord injury (SCI) in adults. Here, we assessed whether deleting PTEN in adult neurons post-SCI is also effective, and whether enhanced regenerative growth is accompanied by enhanced recovery of voluntary motor function. These results indicate that PTEN deletion in adult mice shortly post-SCI can enhance regenerative growth of CST axons and forelimb motor function recovery.

The new study used a gene delivery vector to delete PTEN 20 minutes after a moderate contusion injury at C5. The animals without PTEN could grip and grasp much better than control (injured but untreated) animals.

Why this injury model? From the paper: ... the injury model used in this study was a moderate cervical contusion at C5 centered on the midline of the spinal cord that produced bilateral tissue damage and bilateral function deficits. We chose this injury model for its human relevance. More than 50 percent of spinal cord injuries are at the cervical level, impairing both lower and upper extremities and the most common type of injury in humans is the contusive type. Another thing the scientists wanted to know is if this technique would give the CST axons a boost. The answer is yes, although for reasons that are not clear, CST growth is less than in previous experiments. From the paper: The regenerative growth seen here resembles what has been previously reported following spinal cord injury ... The extent of the regenerative growth appears less extensive, however, although direct comparisons are difficult because the site and nature of the injury are different (C5 contusion vs. T8 dorsal hemisection or crush). Further studies will be required to address this issue.

In conclusion, the present study demonstrates enhanced recovery of forepaw gripping and grasping function and enhanced regenerative growth of injured CST axons with conditional genetic deletion of PTEN in adult mice shortly after a spinal cord injury. These results suggest that manipulations of PTEN or the downstream mTOR pathway may be a viable target for therapeutic interventions to promote axon regeneration after spinal cord injury.