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Consider ideas about outflow pathways, neuroprotection.
This article was reviewed by John R. Samples, MD
Research has provided a fuller understanding of the role of Schlemm’s canal, tissue stiffness, and specifically the importance of flow beyond Schlemm’s canal through the ostia into the collector channels and ultimately the episcleral veins.
The recognition that uveoscleral outflow is now greater than previously thought, ie, it may exceed 50% of all outflow in some patients and the process works for 360 degrees in contrast to the segmental trabecular meshwork (TM) outflow of a few clock hours in most adults.
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The goal is to modify this limitation with drugs, laser, surgery in the form of minimally invasive glaucoma surgeries or other therapies, according to John R. Samples, MD.
Beta-blockers, alpha-adrenergic receptor agonists, and carbonic anhydrase inhibitors have been the mainstays to manage intraocular pressure (IOP).
The popular beta-blockers, however, come with a lot of baggage in the form of systemic adverse effects, low nighttime efficacy, cardiac slowing, and high tachyphylaxis, and their prominence as a treatment of choice has started to wane with the growing prominence of and increased use of prostaglandin analogs and rho kinase inhibitors.
In an ideal world, glaucoma therapy would always be highly efficacious, have the ability to be combined with other therapies, have infrequent dosing, be low cost, have 24-hour IOP control, and provide neuroprotection.
“We also hope that future therapies may structurally alter the retinal ganglion cells [RGCs] and Schlemm’s canal and enhance the trabecular cells. Therapies are destined to become disease altering. That we can actually alter the disease process is the hope given to us by recent advances in cell biology and molecular biology. It is the reason that we have integrated the Trabecular Meshwork Study Club with the American Society for Cell Biology for the past 20 years,” added Samples, a clinical professor at Washington State University’s Elson S. Floyd School of Medicine, in Olympia, Washington.
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New medical therapies
New anti-glaucoma drugs that include the Rho-associated protein kinase (ROCK) inhibitors Rhopressa (netarsudil ophthalmic solution) and Rocklatan (netarsudil and latanoprost ophthalmic solution) (both from Aerie Pharmaceuticals) have been on the US market for over a year, Glanatec (riparsadil, Kowa Company) is in the Japanese market, and the RNAi beta-blocker Bamosiran (Sylentis) is in a phase 2 study.
The highly anticipated adenosine-a1 agonist trabodenoson (INO-8875, Inotek Pharmaceuticals), disappointingly failed at the end of phase 3 trials.
Vyzulta (latanoprostene bunod combined with nitric oxide [NO], Bausch + Lomb), is one of the new prostaglandin analogs already available. Bimatoprost with a NO group attached (NCX 470, Nicox) is making its way through the pipeline, and DE-117 (Santen Pharmaceuticals) is already in a phase 3 trial.
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While the combination of NO and beta-blockers has not panned out, positive effects have been seen when NO was added to travoprost and bimatoprost.
New drugs within reach
Tie2 drugs attach to the Tie2 transmembrane receptor on the endothelial cells. Tie2 functions include maintaining the endothelial cell junctions, inhibiting vascular inflammation, working downstream to activate rho kinase; it also have endothelial NO synthase activity.
Aerpio Pharmaceuticals is developing one such drug, AKB-9778, that is administered subcutaneously, and in addition to activating Tie2, also
is a small molecule inhibitor of vascular endothelial protein tyrosine phosphatase, can elicit signal transduction pathways to mimic netarsudil and latanoprost with NO added.
Another and perhaps an even more promising area of research is examining the proteins in the perfused and non-perfused areas of the TM.
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This research has the potential for a large number of very interesting drug candidates in work done by Drs Janice Varanka and Ted Acott at Oregon Health and Sciences University, Samples pointed out.
Mayo Clinic researchers are exploring potassium-channel openers for modulating IOP. These drugs affect the episcleral venous system, are additive to timolol and prostaglandins, and may provide neuroprotection for RGCs.
Endogenous NO regulates conventional outflow and IOP, which results in relaxation of the TM, opens the extracellular matrix (ECM), and may affect vacuoles in the walls of Schlemm’s canal. The latanoprost marketed with NO has a higher concentration of latanoprost alone.
This in no way detracts from its increased efficacy over routinely used generic latanoprost and prostaglandin than generic latanoprost and may have a possible longer presence in the sclera, which could theoretically act as a reservoir.
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Adenosine-a1 agonists lower IOP; adenosine is distributed throughout the body, especially in the central nervous system and heart. Importantly, the A1 agonists can be neuroprotective if they can access RGCs.
Trabodenoson was the first such drug studied, but it failed as mentioned previously in a phase 3 trial. However, the adenosine agonists and antagonists are one of many classes that may be beneficial to the RGCs.
Future of neuro protection
All All of the previously mentioned therapies have varying potential to be neuroprotective. This can happen through means other than simply the lowering of IOP, which many still believe is the greatest neuroprotection of all.
The rho kinase inhibitors are already used systemically to treat stroke; adenosine drugs, now failed for the purpose of lowering pressure in a phase III trial access the RGCs; and silencing RNA therapy for caspase 2 has been seen to be very promising in small clinical trials.
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Neuroprotection (NO), Samples explained, is an umbrella term that ranges from neuroprotection to neurorescue to neurorejuvenation.
“In glaucoma, a central dogma is that synaptic changes release glutamate leading to excitotoxicity and cellular events that trigger depression of the visual fields leading to cell death,” he said.
NO seems to have a bright future in the area of neuroprotection.
“It is exciting because it activates the TOR genes, which are associated with longevity,” he explained.
There are convincing findings that suggest that manipulating the TOR genes may be associated with canine longevity. In the diet, NO, which is contained in fruit, dark chocolate, and red wine, relaxes the trabecular cells and increases the conventional trabecular outflow.
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ROCK inhibitors block secretion of ECM and possibly act on the ECM in other ways. “It looks as if rho kinase inhibitors can produce long-lasting structural alterations in the TM that extend beyond what one might think,” Samples commented.
Thus far, it has been shown that ROCK inhibitors protect RGCs and prevented fibrosis in cultured human TM cells. Netarsudil was found to reduce elevated IOP caused by steroids in a recent study,1 and Stanford investigators have demonstrated that topical ROCK inhibitors increase RGC survival after trauma to the optic nerve.2
In light of research results with these drugs, which have been used for a long time to treat primary open-angle glaucoma, new uses seem to be in the offing.
Improvements in imaging technologies may be able to demonstrate the neuroprotective effects of these drugs. Moreover, drugs have subtle and potentially disease-altering biologic effects.
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Samples noted that IOP-lowering RCG potential is available with some medications already in use, and cautioned that it is still unknown if they are able to penetrate and reach the optic nerve.
Another promising class of drugs is the growth factors, especially ciliary neurotrophic factor, which is the most promising of these; recombinant human nerve growth factor, and brain-derived growth factor.
“Developments in drug delivery to the optic nerve are coming and should allow us to finally reach the nerve with a new level of certainty,” Samples said.
Finally, a sustained-release pellet (bimatoprost implant, Durysta, Allergan) recently became available that is placed directly into the anterior chamber to lower open-angle glaucoma and works over several months.
Related: Glaucoma drug delivery devices enter new frontier
It is a great example of sustained drug delivery, which may have substantial new benefits from smoothing out IOP fluctuations, Dr. Samples explained.
Long-term studies will hopefully provide reassurance about the corneal endothelium with this exciting new class of implant.
“The future is very bright. We need to be critical of claims forwarded about drugs. Cost is a very high barrier to device approval. Effective devices are available and the other perceived barrier is regulation,” Samples concluded.
Read more by Lynda Charters
John R. Samples, MD
Samples consults and works for Kugler Publications as content architect. He receives royalties from Springer and Healio and for running GlaucomaCME.com, and holds patents with Allergan/Abbvie and Refocus.
1. Price MO, Feng MT, Price FW Jr. Randomized, double-masked trial of netarsudil 0.02% ophthalmic solution for prevention of corticosteroid-induced ocular hypertension. Am J Ophthalmol 2020 Oct 9; doi: 10.1016/j.ajo.2020.09.050. Online ahead of print.
2. Shaw PX, Sang A, Wang Y, et al. Topical administration of a rock/net inhibitor promotes retinal ganglion cell survival and axon regeneration after optic nerve injury. Exp Eye Res 2017;158:33-42.