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Glaucoma Dialogue IGR 12-2

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Comment by Peng Tee Khaw on:

26161 Adenoviral gene transfer of active human transforming growth factor-{beta}2 elevates intraocular pressure and reduces outflow facility in rodent eyes, Shepard AR; Millar JC; Pang IH et al., Investigative Ophthalmology and Visual Science, 2010; 51: 2067-2076

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In their recent paper, Shepard et al. move the evidence of TGF- β2 involvement in glaucoma one step further. By using adenovirus technology and rodents, the authors demonstrate that what is well-established in vitro can now be translated to living animals. Increased levels of TGFβ2 were known to be present in glaucoma patients, reduced outflow facility in perfused cultures, and correlated with increased ECM deposition. Now, the authors show that TGFβ2 can directly increase IOP in vivo.

To deliver an activated recombinant TGFβ2, they introduce known mutations which render the molecule more susceptible to furin-protease. This protease helps converting latent TGFβ2 to its bioactive form. The data is very clear. After a single injection, both rats and mice experiment a statistical significant IOP elevation which matches approximately the expression of TGFβ2. In mice, the elevated IOP correlates nicely with a decrease in outflow facility.

The current trend of using gene transfer to generate glaucoma models is very promising

Since one would think that changes in ECM remodeling would stay around after overexpression and prolong the IOP effect, I would tend to agree more with their second interpretation that the increased IOP is due to TGFβ2 signaling rather than to changes in ECM. In the future, it would be nice to know which delivery site plays a major role. Is it the ciliary body secreting active TGFβ2 and signaling the TM? Or is it the local downstream TM production? The no effect of TGFβ2 wild-type is also an important result. It implicates that the clinical relevance should be placedon the factors that activate TGFβ2 levels, and not on the levels themselves.

Finally, the current trend of using gene transfer to generate glaucoma models is very promising. Adding TGFβ2 to the pipeline of genes to induce elevated IOP widens the possibilities of having, for the first time, a good IOP model with an intact outflow pathway.

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