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Editors Selection IGR 12-1

Basic research: GDNF and loss of neurons

Comment by Robert Nickells on:

19775 Intravitreal injections of GDNF-loaded biodegradable microspheres are neuroprotective in a rat model of glaucoma, Jiang C; Moore MJ; Zhang X et al., Molecular Vision, 2007; 13: 1783-1792

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One of the plausible mechanisms of retinal ganglion cell death in glaucoma is the loss of target-derived neurotrophic support from the brain, presumably caused by impaired axoplasmic transport. In response to this hypothesis, numerous laboratories have attempted to rescue damaged ganglion cells by introducing one or more factors known to have an impact on ganglion cells. These studies have nearly uniformly produced the same result. Firstly, the application of exogenous trophic factors provides a partial (but not complete) rescue of ganglion cells after an insult to the optic nerve, like axotomy. Secondly, the effect is almost always transient, with the protective effect waning the further removed the ganglion cells become from the time of axonal injury. In some cases, the reason for the transient effect is complex. Prolonged delivery of Brain-Derived Neurotrophic Factor (BDNF), for example, yields only a transient effect on ganglion cells partly because these cells down-regulate the BDNF receptor TrkB, making them unresponsive to this survival factor. In some cases, however, the transient effect is more likely caused by an inability to provide a sustained biologically-active dose of the therapeutic agent.

GDNF treatment has the ability to abrogate both retinal and optic nerve pathology

The effect of Glial cell line-Derived Neurotrophic Factor (GDNF) on ganglion cells has been known for many years. Simple intravitreal injections of GDNF have been shown to provide as high as a 30% rescue of ganglion cells that would have normally died two weeks after axotomy. To enhance this effect, GDNF delivery has been modified to include the addition of the TAT peptide, which facilitates the entry of proteins into cells. Exogenous GDNF has also been introduced by gene therapy using both viral-mediated methods and the direct electroporation of GDNF containing plasmids. Jiang et al. (1444) tackle the problem of sustained delivery of GDNF using biodegradable microspheres made of poly DL-lactide-co-glycolide. Similar to an earlier study in which this group injected GDNF microspheres into the vitreous of DBA/2J mice, GDNF containing microspheres were injected into the vitreous cavities of Brown Norway rats with experimental glaucoma. Nine weeks after delivery of the microspheres, during which the rats experienced chronic elevated intraocular pressure, the glaucomatous eyes were examined for a variety of parameters of optic nerve and retinal pathology. Perhaps the most important finding of this study was the dose-dependent attenuation of ganglion cell soma and axon loss relative to eyes injected with empty microspheres or buffered saline solution. Eyes receiving empty microspheres or saline suffered a 65% loss of neurons in the ganglion cell layer, while eyes receiving the highest dose of GDNF microspheres exhibited only a 36% loss of neurons. Similar levels of axonal loss were also observed, indicating that the GDNF treatment has the ability to abrogate both retinal and optic nerve pathology.

Currently, there is no clear explanation of how GDNF is able to affect ganglion cell survival. The authors speculate that there may be both direct and indirect effects of this neurotrophin. Ganglion cells appear to express the GFRβ-1 and GFRβ-2 receptors, along with the Ret tyrosine kinase receptor. Alternatively, there also appears to be a dose-dependent suppression of retinal and optic nerve glial cell activation in this experimental paradigm. Whatever the mechanism, the use of biodegradable microspheres may hold a great deal of promise for the sustained delivery of biological therapeutic molecules like GDNF.

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