Combined Therapies in the Treatment of Neurotrauma: Polymers, Bridges and Gene Therapy in Visual System Repair

Abstract

Background: The mature central nervous system (CNS) has limited capacity for self-renewal and repair after injury or neurodegeneration, and therapeutic strategies are needed to promote the viability of damaged neurons and the regrowth of their axons. The retina and optic nerve (ON) are part of the CNS, and the visual system is widely used in experimental studies on injury and repair. Objective:To test various cellular and molecular approaches in attempts to replace retinal ganglion cells (RGCs) in depleted retinas or, more usually, promote the survival of endogenous injured RGCs and stimulate axonal regeneration after ON or intracranial optic tract (OT) injury. Methods and Results: Intraocular injections of brain-derived neurotrophic factor and ciliary neurotrophic factor (CNTF) temporarily increase RGC survival after ON injury. More sustained neuroprotection is obtained using adeno-associated viral vectors to transfect RGCs with brain-derived neurotrophic factor or CNTF genes. After ON crush, intravitreal adeno-associated viral CNTF injections also increase RGC axonal regrowth. Additional protective and growth effects are obtained after intraocular elevation of cAMP and by manipulation of protein kinase signalling pathways in RGCs. Regeneration is increased by transplanting a segment of peripheral nerve onto the cut ON. Schwann cells in peripheral nerve grafts can be genetically modified using lentiviral vectors to over-express CNTF, resulting in increased regrowth of RGC axons. After OT lesions, hydrogels have been used to bridge the injury, sometimes with the incorporation of signalling peptides or cells genetically modified to express neurotrophic factors. Conclusions: There is now a general consensus that combinatorial approaches are needed to elicit sustained and effective regenerative responses in injured adult CNS neurons.