The 4 P's of CNS regeneration: A framework for approaching the repair of neural trauma using nanotechnology and combination therapies

Abstract

Until recently functional recovery of damaged CNS was an unattainable goal and nanotechnology was an invisible science. As in life there are no magic bullets, but a well planned treatment spaced over time may bring about functional return in the CNS. The Four P’s of CNS regeneration is a new framework for approaching CNS injury. The four components are: Preserve, Permit, Promote and Plasticity.

The determining factor in functional recovery was once thought to be the amount of re-innervation. However, it is now known that the level of recovery is determined not only by the number of axons but also the local density of their connections as well as the rehabilitation work done to drive reinnervation and refinement through training. There are four distinct issues that need to be addressed in order for successful CNS regeneration to occur: 1. Preserve - How can neurons with damaged axons be kept alive long enough to regrow and obtain functional regeneration? 2. Permit - How can a permissive environment be created that will allow axons to grow through the site of the lesion? Using the mammalian visual system as a model, we report that a designed self-assembling peptide nanofiber scaffold in combination with ABC creates a permissive environment not only for axons to regenerate through the site of an acute injury, but also to knit the brain tissue together in both young and adult animals. 3. Promote - How can axon growth be promoted in the correct direction coincident with the onset of the permissive environment? Combination of SAP and CNTF is shown to offer an effective new means of creating a permissive environment for axonal growth while CNTF promotes growth of axons across this environment in tissue disruptions caused by traumatic injury to the CNS, allowing regrowth of axons into the SC and functional return of vision. 4. Plasticity - How can changes in morphology in-vivo be promoted so the axon connections are functional in the target, mapped correctly and are in sufficient amount to drive behavior? Behavioral testing of animals drives plasticity and rewiring of the brain in the superior colliculus