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Mechanisms of AAV Transduction in Glaucoma-Associated Human Trabecular Meshwork Cells
Yeni Yücel and Neeru Gupta, winners WGA Award 2006
Neuroprotective strategies to protect and rescue retinal ganglion cells from death in glaucoma are under active investigation. Traditionally, following their delivery to the retina and optic nerve, the effectiveness of candidate neuroprotective molecules or genes is measured by reporting numbers of surviving retinal ganglion cells.
We suggest that in addition to targeting RGCs in the eye, treatments for glaucoma should consider protecting RGC axon portions outside of the eye, where the majority of the cell axon lies. The RGC axon forms portions of the intraorbital, canalicular, intracranial optic nerve, optic chiasm and the optic tract, until terminating in the major target vision center of the brain, the lateral geniculate nucleus (LGN). There is evidence in experimental primate and human glaucoma that axon injury may lead to injury and degeneration of target LGN neurons.
The loss and shrinkage of LGN neurons in glaucoma is compelling evidence for
developing treatments for glaucoma that are attentive to the RGC cell body, its
extra-ocular axonal components, in addition to its target neurons in the brain.
Thus, treatments for neurodegenerative diseases may also be relevant to preventing transsynaptic CNS degeneration
in glaucoma, such as memantine, approved for Alzheimer's disease. Memantine is an
open channel NMDA glutamate blocker that crosses the blood brain barrier. In this
context, the effectiveness of memantine as a neuroprotective agent in glaucoma was
assessed, with LGN neurons as the treatment target, and LGN cell shrinkage as the
outcome measure and indicator of injury in surviving neurons.
Memantine showed a significant protective effect on neuron size in surviving LGN
neurons of experimental primate glaucoma compared to vehicle treated primate glaucoma, in spite of no significant effect on LGN
neuron numbers. Furthermore, the protective effect of memantine on cell size was
observed in magno- and parvocellular pathways, with a greater effect on magnocellular
neurons, using RGC loss as a covariate.
There are a number of implications of this study. The first is that neuroprotective agents for glaucoma should consider eye and brain targets. The second is that while measurement of neuron death as a measure of treatment effectiveness is standard, measurements of relative states of health among neuron survivors can provide information regarding dysfunction or injury that would otherwise be missed with an `all or none' approach. A third point is that LGN neuron injury in glaucoma as a treatment target, offers an additional outcome measure to understand injury and prevention in glaucomatous disease. Because of the exquisite organization of the LGN, there is also the potential to determine injury to neuron populations with specific functional attributes. Finally, the attenuation of shrinkage in LGN neurons by memantine in experimental glaucoma implicates the glutamatergic system in transsynaptic degeneration in glaucoma.
Elevated IOP and injury to RGCs can trigger degeneration in distant connected neurons in major vision centers of the brain. Secondary pathological changes in the brain may be in part responsible for progressive vision loss despite adequate IOP control. Thus, IOP lowering strategies combined with therapies to protect the retina and central visual system pathways is a rational approach in glaucoma. The LGN in glaucoma may be considered a novel target to be considered in the study of future neuroprotective agents, in addition to new outcome measures of success such as LGN neuron size, a marker of cell injury in glaucoma shown to correlate with optic nerve damage. A drug that is not directed at lowering intraocular pressure, but rather directed at blocking glutamate excitotoxicity, was protective of adult visual neurons of the brain in this pressure induced glaucoma model. These findings may be relevant to help prevent blindness from glaucoma.
Co-authors: Q. Zhang, A.P. Mizisin, M.W. Kalichman and R.N. Weinreb