A Glimpse Over the Horizon

When it comes to open-angle glaucoma, up to 10 percent of patients are not optimally responsive to current topical pressure-reducing medications; moreover, patient compliance is not an insignificant issue. In other words, there is room to improve.

Interestingly, the majority of medications in use today do not primarily target the major (conventional) aqueous outflow pathway – where aqueous humor drains through the trabecular meshwork (TM) into Schlemm’s canal (SC), and thus into the episclearal veins. Rather, they inhibit aqueous production by the ciliary body, or enhance its removal through the minor (uveoscleral) route. Much commercial interest therefore lies in the development of formulations that are more active on conventional outflow, and, indeed, such formulations have now emerged (Rhopressa) (1).

Glaucoma can be legitimately classified as a progressive retinopathy, elevated intraocular pressure-inducing degeneration at the optic nerve head with concomitant demise of the retinal ganglion cells. However, it is essentially unique among retinopathies in that the primary cause of the disease lies within the anterior portion of the eye, where aqueous drainage through the TM and SC is compromised, resulting in IOP elevation.

So far, no genetically-based therapeutics have been approved that target the primary outflow tissues (or indeed any aimed at protecting the viability of the ganglion cells), but there are signs on the horizon. The retina has been prominent as a target for gene therapy, principally because viral delivery systems (and especially, adeno-associated virus [AAV] vectors) can be introduced into the eye by the sub-retinal route. Proof of the point lies in the first FDA/EMA approval for a gene therapy targeting individuals with the inherited retinopathy, Leber congenital amaurosis (2).

Though tissues of the conventional outflow pathway have proven difficult to transfect with standard AAV vectors (1, 3), success has been seen with self-complementary AAV vectors (4, 5). In addition, AAV-Anc80L65, with its synthetically-designed capsid and a single-stranded genome, has also recently been shown to transfect tissues of the anterior chamber with high efficiency (6).

AAV9 has been similarly shown to transfect corneal endothelium in a highly efficient manner, and we recently reported a strategy for enhancement of outflow facility using this approach (7). Here, AAV9 expressing a matrix metalloproteinase (MMP3) transfects the corneal endothelium of mice (following a single intracameral inoculation), essentially rendering the endothelium a cellular factory for the expression of secretory proteins, which may then enter directly into the anterior chamber.

An entirely different approach recently reported by Tam and colleagues targeted SC itself with small-interfering siRNA (8). Aqueous humor funnels through the TM, converging on the endothelial cells lining SC; fluid then enters the canal either through the formation of vacuoles in endothelial membranes or through the spaces/clefts left between the tight junctions joining the endothelial cells together. By intracamerally inoculating rodents with siRNA targeting transcripts encoding selected tight-junction components, Tam and colleagues saw a subsequent widening of the clefts and an enhancement of canal permeability. Treatment of acute elevations in IOP could be one application of this approach.

It is of interest to note that siRNA delivery systems have recently been enhanced using nanoparticles that increase target specificity (9). In this study, researchers took advantage of the fact that TM and SC cells express the surface marker CD44. The polysaccharide hyaluronan can be used to target CD44, and so siRNA encapsulated in nanoparticles coated with hyaluronic acid allow for smaller amounts of siRNA to be efficiently delivered to these tissues.

Both siRNA and AAV vectors are accepted modes of ocular therapy. I’m personally excited that the advanced approaches shared here – and others like them – could hold significant potential in the future management of elevated IOP.