Gene therapy for central nervous system repair.

The amelioration of the sequelae of CNS injury by gene therapy requires three post-injury events to be addressed: scarring, neuron death and axon regeneration. Administering anti-apoptotic, and axon growth promoting genes to neurons is inefficient, using nonviral vectors, because access to the transcriptional machinery is restricted by an intact nuclear membrane in G0 cells. Viral vectors have better transfection rates but a higher incidence of deleterious effects than non-viral vectors. Discrete targeted transfection of astrocytes, for example, about the wound with antifibrotic genes is essential to control scarring and for the inhibition of axon growth locally by gene products without transfecting neighboring and distant cells. Either rational or forced evolutionary design of vectors will ultimately achieve efficient safe gene transduction. Recombinant protein treatments for CNS repair have proved disappointing, probably because axotomized neurons are difficult to access in multiple disparate sites in the CNS after penetrant injury. Gene therapy has the potential to overcome these difficulties since sustained antiscarring/neurotrophic regimes are achievable after a single delivery to the site of injury by uptake by local injury responsive cells in the wound, and by axon terminals. Subsequent retrograde axonal transport delivers the therapeutic genes to all axotomized neurons throughout the CNS.