Use of a Viral Vector Approach to Delete PTEN in the Motor Cortex and Promote Axon Regeneration after Spinal Cord Injury
Oswald Steward, Ph.D., UC Irvine
Director & Professor, Reeve-Irvine Research Center; Professor, Departments of Anatomy and Neurobiology, Neurobiology and Behavior and Neurosurgery

Most of the symptoms resulting from spinal cord injury are due to the interruption of the long tracts that interconnect the brain and spinal cord. Thus, promoting regeneration of these tracts is considered a clinically relevant approach to advancing recovery of motor function in patients with spinal cord injury. Previously published data indicate that suppression of cellular signaling by phosphatase and tensin (PTEN) induces a regeneration competent state in adult CNS neurons [8]. Recently, Zhigang He and colleagues (Children’s Hospital/Harvard) in collaboration with members of the Steward laboratory have examined the impact of specific deletion of PTEN from the motor cortex on cortical spinal tract (CST) axon regeneration in mice with spinal cord injuries (SCI). Data from these studies demonstrate that PTEN deletion from the motor cortex promotes striking regeneration of axons past the injury site in mice with either thoracic dorsal hemisection or thoracic crush injuries. Here, our goal is to develop a clinically relevant approach in which endogenous PTEN expression can be selectively suppressed in the motor cortex of rats at the time of- or soon after spinal cord injury, an approach that could eventually be used in human therapy. In these experiments we will administer an adeno-associated viral (AAV) vector expressing a short hairpin RNA sequence against PTEN to rats with spinal cord injury. We will then evaluate (i) the extent of PTEN suppression in the motor cortex, (ii) CST axon extension and regeneration, and (iii) recovery of motor function after spinal cord injury.

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