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Glaucoma Dialogue IGR 12-2

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Comment by Tina Wong 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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The family of ubiquitous proteins known as the transforming growth factor-beta (TGF-β) are of great relevance to glaucoma specialists. Because they induce many cellular functions that are associated with matrix formation and scarring , they have importance in everything from subconjunctival scarring and failure of glaucoma filtering surgery, cataract formation, optic nerve damage and in the case of this reviewed article, aqueous humour outflow. As the literature pertaining to the role of the TGF-β2 isoform in the pathogenesis of human primary open-angle glaucoma continues to expand, this article by Shepardet al. provides further evidence in an animal model to suggest that TGF-β2 is responsible for inducing a rise in intraocular pressure (IOP) that may be due to an effect upon the aqueous outflow facility. However the study itself raises several further questions that need to be addressed in order to understand the mechanism by which this process occurs.

The in-vitro assays of the TGF-β2 gene constructs transfected into both hamster ovary and human trabecular meshwork cells, convincingly demonstrate that the total and active isoforms of TGF-β2 are increased at 48 hours when compared to control, in particular with the gene construct designed to induce mutations in the latency associated peptide. It would be interesting to know whether this effect is long lasting in vitro - this may help provide further information on the efficacy of the adenoviral transductions which in turn may provide an alternative explanation for the transient IOP rise seen in vivo. Clearly TGF-β2 levels in the aqueous are increased following transfection, but this raises two questions. Firstly which major cell type(s) is/are transfected to produce the active cytokine, and secondly is the active cytokine having any other effects elsewhere that may influence the IOP equilibrium? It would be helpful to examine the ciliary epithelium and to investigate whether there has been any TGF-β2 mediated effect upon aqueous production.

TGF-β and agents that modulate its effect could still yet play a role in the management of glaucoma

This paper elegantly demonstrates impairment in the aqueous outflow facility of eyes transfected with the activated TGF-β2 construct. We can only speculate on the actual mechanism by which TGF-β2 induces an IOP rise. It is presumed that TGF-β2 induces matrix deposition and change including polymerisation of fibronectin within the trabecular meshwork. With such a mechanism, one would expect to observe a longer lasting rise in IOP due to the mechanical changes in the outflow facility. It would be interesting to study both the conventional and uveoscleral components to aqueous outflow to see how these vary following overexpression of TGF-β2.

The transient ocular hypertensive response has been attributed to a host immune response to viral proteins negating the effects of the transfection. We look forward to the results of the authors' experiments to prolong this effect to around five months using an anti- CD40L antibody, but it may be better to proceed with other vectors such as AAV, that are associated with minimal host responses, as used in the recent ophthalmic gene therapy trials.

Despite the promise that TGF-β2 has in developing animal models for open-angle glaucoma, the problems associated with long term overexpression of TGF-β2, such as peripheral anterior synechiae and cataract, could prove an obstacle in developing an animal model for a chronic condition such as glaucoma. Finally, this paper continues to emphasise that TGF-β and agents that modulate its effect could still yet play a role in the management of glaucoma.

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