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.

Cellular tropism and transduction properties of seven adeno-associated viral vector serotypes in adult retina after intravitreal injection

“…Intravitreal injections for the treatment of photoreceptor dysfunction may have advantages, including capacity for larger, as well as multiple, vector injections and possible combinations with other pharmacotherapeutic agents. 9,10,[27][28][29][30][31] In our hands, rAAV2/1, rAAV2/4, rAAV2/5 and rAAV2/8 were the least efficient among the tested vectors. Earlier studies based on fluorescent intensity measurements have also shown low transduction efficiencies for these vector types; 4,7,8,12 however, when injected subretinally, others have reported that rAAV2/ 8 is efficient, even for transducing RGCs.…”

“…A larger vector volume can be delivered and this approach also allows repeated injections, and can thus be combined with the delivery of other pharmacotherapeutic agents. 9,10,[27][28][29][30][31] The ability to target photoreceptor cells in the outer retina through intravitreal injections may therefore be of clinical benefit.…”

Multiple transcription factor families regulate axon growth and regeneration

“…Other treatments using CNTF have been performed to increase axon regeneration in RGCs (for review, Harvey,2007). Although not directly showing a dependence on STAT3, these results suggest that CNTF application followed by increased activated STAT3 may increase axon regeneration in RGCs.…”

Isolated unilateral disk edema

“…After physiological damage, retinal ganglion cells (RGC) within the optic nerve -like neurons elsewhere in the CNS 77,78 -die by the process of apoptosis, a programmed cell death. 79 Although RGC death may not occur immediately after the pathological insult, 80 eventually, apoptosis appears to be a final common pathway for all optic neuropathies.…”