Glaucoma is an optic neuropathy in which at least one eye has accelerated ganglion cell death characterized by excavated cupping appearance of the optic nerve with progressive thinning of retinal nerve fiber layer tissue and corresponding subsequent visual field loss.

Primary Open Angle Glaucoma is the most common type of glaucoma. An increase in eye pressure, intraocular pressure (IOP), occurs slowly over time leading to vision loss.

Higher IOP is thought to be the result of changes in the eye that lead to an obstruction in the outflow of fluid. Large clinical studies have shown that, with reduction in IOP, retinal damage and progressive visual loss can be slowed or minimized.

Treatments to reduce IOP rely on topical eye drop medications, laser and or conventional surgery. Many patients require more than one drug to control IOP, and despite effective current therapies, they don’t work for all patients.

Current drug treatments are directed towards lowering IOP. Conventional glaucoma medications (beta blockers, alpha agonists, or carbonic anhydrase inhibitors) lower IOP primarily by reducing the production of aqueous humor, primarily reduce the production of aqueous humor, whereas prostaglandin analogs decrease IOP by increasing uveoscleral outflow, usually a secondary outflow pathway. Prostaglandins, are now the most prescribed glaucoma treatment worldwide. There are also products that combine different classes in one bottle.glaucoma gl

A new class of glaucoma drugs promises to act specifically on the eye’s drainage canals, called the trabecular meshwork, a main outflow and blockage site in glaucoma. Rho kinase (ROCK) inhibitors target cells in the trabecular meshwork to enhance aqueous humor outflow. Aqueous humor is a clear fluid that maintains the intraocular pressure.

In research models of glaucoma, ROCK inhibitors have been shown to reduce cellular “stiffness” and enhance outflow through the trabecular meshwork, thereby reducing IOP. No drugs currently on the market enhance the eye’s fluid outflow in this way. Therefore this is a novel and unique target and approach to lowering IOP.

ROCK inhibitors are not yet approved and available for glaucoma patients. Two US companies, Aerie and Altheos, are currently in early clinical research development with topical ROCK inhibitors to lower IOP.

Research data has shown that ROCK inhibition has the potential to offer neuroprotective and anti-inflammatory effects as well as enhance blood flow to the optic nerve, all of which could benefit glaucoma patients. The glaucoma community looks forward to and awaits the clinical research data as it becomes available for this potentially exciting class of drug compounds.glaukoma

The topical medication Ripasudil (K-115, Kowa) has been shown to reduce IOP significantly for at least seven hours with twice-daily dosing. It was recently approved in Japan as an adjunct to prostaglandin analogs.

The product candidate that has advanced furthest through clinical trials in the United States is the compound AR-13324 (Rhopresa, Aerie Pharmaceuticals), which is in Phase 3 registration trials. In a recently completed study, Rhopresa was also found to reduce episkleral venous pressure (EVP), an important contributor to IOP, particularly at low pressures.

Although mutations in several genes, including myocilin, optineuron, and CYP1B1, have been reported to cause POAG, these genes account for less than 10% of cases worldwide. Myocilin belongs to a family of olfactomedin domain-containing proteins numbering at least 13 in mammals.

Myocilin is a protein common to parts of the eye and other neural tissues.

In mutant forms, this protein contributes to glaucoma.

Genetic mutations cause it to become misshapen through a process known as “protein misfolding”. That, in turn, triggers production of fibrous amyloid residue that clog the drainage channels of the eye. The amyloid-containing myocilin deposits we discovered kill cells that maintain the integrity of TM.

Based on these findings, new research may look for drugs that prevent or stop myocilin amyloid formation or destroy existing fibrils in glaucoma patients. "These are really the first potential drug targets for glaucoma," researchers said.glaukommm

The impact of ROCK or ROCK/NET inhibitors on the future of glaucoma therapy remains to be seen. But it is exciting to have novel treatments with new mechanisms of action in development that may eventually provide durable and consistent IOP-lowering with the potential to modify the course of a disease that remains a leading cause of blindness.

References:

  • http://www.glaucoma.org/treatment/new-class-of-glaucoma-drugs-on-the-horizon.php,
  • http://www.brightfocus.org/glaucoma/news/mutant-forms-protein-contributes-glaucoma,
  • http://www.news-medical.net/news/20140124/Scientists-identify-molecules-that-block-accumulation-of-toxic-eye-protein-responsible-for-early-onset-of-glaucoma.aspx,
  • http://med.miami.edu/news/bascom-palmer-researchers-discover-protein-that-leads-to-glaucoma,
  • http://www.ophthalmicprofessional.com/articlevjenwer.aspx?articleID=112374.