Glaucoma Opinion IGR 13-4

Glaucoma Models

John Danias

Ex-vivo and in-vivo models have been used for understanding glaucoma. Disease models are not unique for glaucoma. They allow a defined environment for testing specific hypotheses on disease pathophysiology and provide a system for testing the therapeutic potential of specific interventions. At their simplest form, disease models can be subcellular systems or cells in culture. However, cell, tissue and organ cultures cannot accurately represent the complexity of a living organism environment. They are useful for understanding mechanisms at the molecular level but should be considered mainly as a starting point. In addition cell, tissue and organ cultures often cannot be created without inducing damage to the relevant tissues and cannot be used for long-term studies. Animal models are well suited for creating hypotheses especially in complex disease where more than one tissue/organ is involved. As such many animal models have been developed for glaucoma research. It is useful to consider these models in two main groups depending on the particular aspect of glaucoma pathophysiology that is being investigated/modeled. One group has to do with modeling aqueous flow dynamics and IOP control, while the other with modeling the neurodegenerative aspects of the disease. Although a detailed description of the various animal models of glaucoma are beyond the scope of this brief synopsis, certain features of the various glaucoma models can be summarized.

Spontaneous glaucoma models have been described in mice (DBA/2 and other mouse strains), in rats, rabbits, dogs and primates. All share high IOP that often results in eye enlargement and progressive loss of retinal ganglion cell axons. The advantages of spontaneous models is that they do not require experimental intervention, they occur over long periods of time and they most closely mimic the important aspects of the human disease. As one moves to higher species, similarities to human disease become more pronounced, but mice offer the potential to use the power of genetics to elucidate disease pathophysiology.

Mice offer the potential to use the power of genetics to elucidate disease pathophysiology

However, the long duration of disease development is a double-edged sword as it increases the time required to observe the effects of experimental interventions. In addition disease development is generally asynchronous and often-time variable even in inbred animal strains.

Induced glaucoma models have been described in mice, rats, rabbits, cats, dogs, sheep, cows and primates. IOP elevation is usually acute and achieved by obstructing the outflow pathways (exceptions are the steroid-induced IOP elevation in ruminants and cats). Time course for induction of retinal ganglion cell and axonal loss (when it occurs) is shorter than in spontaneous models and more importantly it is synchronous. This allows for more robust testing of specific hypotheses on effects of IOP elevation. However induced models are admittedly further away from human disease than spontaneous ones. Despite the uniformity of the experimental intervention to induce glaucoma-like pathology many of these models still have large inter-animal variations.

In addition to the particular model utilized, one has to also pay attention to the study endpoints. For example measuring IOP is not equivalent to measuring outflow facility or to measuring morphologic changes at the trabecular meshwork. Similarly measuring RGC loss is not the same as measuring axonal loss. Even the specific methods used to measure the same endpoint can provide different answers. Counting for example RGCs labeled by fluorogold, Thy1, Brn3 or gamma-tubulin is not the same.

It is thus important to realize that all animal models of glaucoma, as well as the methodology associated with them (and for that matter in-vitro models of the disease as well), have inherent strengths and weaknesses that affect their usefulness.

All animal models of glaucoma, as well as the methodology associated with them, have inherent strengths and weaknesses that affect their usefulness

Understanding the strengths and weaknesses of each model system is critical in both selecting the most appropriate model for the type of study contemplated and interpreting the results of experimentation. It is particularly important to try to confirm results generated using a specific model using other (ideally multiple and in different species) unrelated models of the disease. Such confirmation provides credence to experimental results and suggests that they are caused by common underlying mechanisms that are likely to be present in humans as well. Ultimately, confirming these findings (or their implications) in human specimens is critical for ensuring the relevance of discoveries.

Issue 13-4

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