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Editors Selection IGR 16-1

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Comment by Nils Loewen 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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Shepard et al. showed a persuasive association between increase in TGF-β2 levels and ocular hypertension possibly via decreased AH outflow. However, the described method of injecting TGF-β2- expressing adenoviral vectors into rodent eyes to generate a model for POAG may be premature or limited, provided several key issues are resolved. We are, first of all, rather concerned about the wellknown effect of adenoviral infection on the inflammatory response. The problem is that most of the in-vivo data shown in this study, be it the effect on TGF-β marker gene expression or AH outflow facility, were all compared against uninjected eyes and not eyes injected with the empty adenoviral vector. Viral-induced effects, as opposed to transgene expression effects, on the reported observations were not shown in the report. TNF-β induction is perhaps the most wellknown 'side-effect' to the introduction of adenoviral vectors into mammalian systems. While it is known that thalidomide, a TNF-β inhibitor, affects latanoprost regulation of IOP, it is unclear how TNF-β itself affects IOP. Although the authors showed a clear difference in the IOPs between TGF-β2-transduced versus empty adenoviral vectortransduced eyes, the alteration in IOP seen in the TGF-β2-transduced eyes may be a combination of the effect of TGF-β2 and perhaps other inflammatory cytokines like TNF-β which may act synergistically or even in an opposing manner to TGF-β2. Hence, the observed IOPs may be the result of far more complex mechanisms than simply due to the effects of increased TGF-β2 levels alone. Additionally, TNF-β is implicated in the apoptotic death of retinal ganglion cells in glaucoma patients and hence the described method may not be suitable for dissecting the role of TGF-β2 in causing optic nerve head degeneration in glaucoma. Moreover, the described method suggests that it is almost impossible to control the level and where the injected eye expresses the transgene. This can present problems for investigators since, in any given study, injected eyes would feature varying levels of TGF-β2 (and the concomitant changes in IOP) and a spectrum in eye anatomy alterations. This may make it challenging to tease out the contribution of individual ocular tissue response to changes in IOP or establish unequivocably the mechanistic effect of candidate therapeutics for POAG.

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