HSV-mediated Gene Transfer of C3 transferase Inhibits Rho to Promote Axonal Regeneration

Exp Neurol, 2012 · DOI: 10.1016/j.expneurol.2012.06.016 · Published: September 1, 2012

Regenerative Medicine Neurology Genetics

Simple Explanation

Trauma to nerves can cause lasting damage, and while peripheral nerves can regenerate, central nervous system regeneration is blocked. This study uses a virus to deliver a gene into nerve cells to promote regeneration. The delivered gene codes for C3 transferase, which inhibits Rho GTPase. Inhibiting Rho GTPase can overcome the inhibitory effects of myelin and glial scars, promoting nerve regeneration. The study found that delivering C3 transferase via a herpes simplex virus vector enhanced axonal regeneration into the spinal cord and improved sensory-motor coordination in rats after nerve injury.

Study Duration

7 weeks

Participants

Sprague–Dawley rats

Evidence Level

Not specified

Key Findings

1
HSV vector vC3t produces C3 transferase (C3t) in vitro and in vivo, inhibiting Rho GTPase activity in DRG neurons.
2
vC3t enhances sensory regeneration into the dorsal horn of the spinal cord after cervical rhizotomy, promoting growth of both unmyelinated and myelinated fibers.
3
Subcutaneous inoculation of vC3t improves forelimb function, as measured by grid walk and cylinder tests, following dorsal root injury.

Research Summary

This study investigates the use of a herpes simplex virus (HSV) vector to deliver the C3 transferase (C3t) gene into dorsal root ganglion (DRG) neurons to promote axonal regeneration after cervical root injury. The expression of C3t inhibits Rho GTPase activity, overcoming the inhibitory effects of myelin and glial scars, and leading to enhanced axonal regeneration into the spinal cord. The results demonstrate that vC3t enhances sensory regeneration, improves forelimb function, and represents a promising therapeutic tool for treating nerve injuries.

Practical Implications

Therapeutic Potential

HSV-mediated gene transfer of C3 transferase could be a potential therapeutic strategy for promoting axonal regeneration and functional recovery after nerve injuries.

Targeting Rho GTPase

Inhibiting Rho GTPase activity is a viable approach to overcome the inhibitory effects of myelin and glial scars on axonal regeneration.

Combination Therapies

Combining vC3t with neurotrophic factors could offer additional advantages in enhancing regeneration by both blocking RhoA inhibition and increasing cAMP-PKA and ras-MAPK signaling.

Study Limitations

1
One of the limitations in the use of recombinant C3t to enhance regeneration after injury is the possibility of off-target effects resulting from inhibition of RhoA activity in uninjured neurons.
2
No CTB labeling was seen in the medulla suggesting that axons had not reached the nucleus cuneatus at the time of study 8 weeks.
3
Developments in the regulation of expression cassettes from HSV vectors may provide additional advantages towards the treatment of these chronic neurologic conditions

Your Feedback

Was this summary helpful?

Back to Regenerative Medicine