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Glaucoma Dialogue IGR 12-2

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Comment by Hari Jayaram 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 this study, adenoviral vector transduction of mutationally bio-activated human TGF-β2 caused elevated IOP in rats and mice. The significance is two-fold.The data show in a well-controlled way that this signaling molecule, previously implicated by a variety of in-vitro and in-vivo observations, can indeed produce IOP elevation in both animals. Secondly, it is a step towards what has been an important yet remarkably elusive goal: animal mode that recapitulate main features of human POAG, in particular the subtle physiological derangements in aqueous humor dynamics. Regarding the quality of the data, there is much to like: validation of mutations that generate spontaneously bioactive human TGF-β2, systematic documentation of the vector expression properties prior to the animal work, the inclusion of strong correlative data in Figures 5, 6 and particularly 9, where outflow facility was tested specifically, and the clearly significant effect on IOP (it was doubled in mice and raised significantly in rats, whereas the control vector had no effect). The caveats are perhaps largely attributable to the vector itself. Although more sustained expression in vivo in a variety of tissues (liver, muscle) has been observable with some adenovirus vectors, e.g., helper-dependent versions devoid of all coding regions, in general these vectors have been more suited to transient over-expression, as seen here. Thus, after the initial rise in IOP within the first week in both rats and mice, it fell again to close to baseline levels within a week in the rat and within two weeks in the mouse (Fig. 4). A second issue with these vectors is their tendency to be relatively inflammatory. Figure 7 gives us some suggestion of this, and there was an increase in corneal thickness. Importantly however, the rigorous control design chosen by the authors, in which the control vector was entrained through all studies in parallel, rules out the vector as a cause of IOP elevation and pinpoints TGF-β2 itself. In the future, moving to other vectors capable of producing sustained and ideally very long term moderate-level expression in the non-dividing tissues of the eye, such as lentiviral vectors, may be fruitful for modeling this chronic disease.

A final interesting question going forward is how the precise location of TGF-β2 expression within the anterior segment determines its effects. Figure 5B shows elevated aqueous humor levels. Will IOP elevation be maximal with high local TM expression itself (presumably the majority of the transduction here occurred in TM) or by engineering secretion of TGF-β2 to be secreted into aqueous humor upstream of the TM?

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