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Active research in neuroprotection, neuroregeneration, and sustained drug delivery is expected to lead to better options for management of glaucoma.
Take-home message: Active research in neuroprotection, neuroregeneration, and sustained drug delivery is expected to lead to better options for management of glaucoma.
By Cheryl Guttman Krader; Reviewed by Christopher A. Girkin, MD, MSPH, and Harry A. Quigley, MD
Though neuroprotective and neuroregenerative treatments will be part of glaucoma management in the future, IOP-lowering therapies will continue to have an important role, according to two glaucoma specialists.
“Neuroprotection for glaucoma is coming, and it is matter of when it will happen, not if,” said Harry A. Quigley, MD, director, Glaucoma Center for Excellence, and A. Edward Maumenee Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore.
Noting that IOP lowering itself can be neuroprotective, Dr. Quigley predicted that products based on sustained delivery of currently available IOP-lowering medications will likely become available sooner than any neuroprotective medications with novel mechanisms of action.
He also anticipated the eventual availability of neuoregenerative approaches for glaucoma management, noting that ideally, however, glaucomatous damage will be prevented rather than need fixing.
Dr. Quigley pointed out that there are a variety of factors limiting neuroprotective benefit with use of topical IOP-lowering medications. Of those, inadequate patient adherence and treatment-related side effects are two issues that could be overcome with sustained drug delivery, which would eliminate the need for drop administration and expose the eye to a safer, lower concentration of medication.
Sustained delivery also offers an opportunity to use medications that are not currently amenable for topical therapy because of their potential corneal toxicity.
Aside from sustained delivery formulations of IOP-lowering drugs, Dr. Quigley suggested there may be neuroprotective agents for glaucoma in the not-too-distant future acting by a variety of other mechanisms. Research to date includes studies of treatments aiming to prevent injury to the retinal ganglion cell (RGC) body or axon, modulate connective tissue in the sclera and lamina cribrosa, improve autoregulation of blood flow, and mitigate glial cell cytokine release.
Dr. Quigley noted that his group recently published on the use of an inhibitor of dual leucine zipper kinase (DLK), a protein that is upregulated in response to RGC axonal injury and a key mediator of RGC death. Their study, conducted in a rat glaucoma model, showed that intravitreal injection of a small molecule DLK inhibitor in a nanoparticle formulation blocked RGC death for 5 to 6 weeks.
Earlier work from Dr. Quigley’s lab showed gene therapy with brain-derived neurotrophic factor or ciliary neurotrophic factor (CNTF) protected the RGCs in a rat glaucoma model. Referring to the investigational implant of CNTF-secreting human cells (NT-501 Encapsulated Cell Therapy, Neurotech), Dr. Quigley noted that it has shown promising efficacy in early clinical research and has an advantage of being removable if there is any concern about adverse events.
He also discussed research his group has been conducting that focuses on manipulating IOP-related stress and strain in the scleral wall and lamina cribrosa as a means of protecting against RGC axonal injury.
Most recently, results of a study in a mouse model of glaucoma showed that RGC axon loss was significantly reduced in animals treated with oral losartan compared with controls treated with spironolactone or placebo. The findings were presented at the 2015 meeting of the Association for Research in Vision and Ophthalmology.
Losartan is commercially available for treating hypertension and other indications. It is an angiotensin 1 receptor inhibitor that also inhibits transforming growth factor-beta activity.
“We believe this type of treatment might be delivered locally on a chronic basis to the eye,” Dr. Quiglely said.
The ability to demonstrate efficacy of a neuroprotective agent for glaucoma in humans is difficult for a variety of reasons, including the slowly progressive nature of the disease. However, the challenge is not insurmountable, judging from a recently published randomized controlled study that demonstrated a benefit of topical prostaglandin analogue treatment for preventing visual field loss after just 2 years of follow-up.
Thus, Dr. Quigley proposed that it should also be possible to demonstrate efficacy for any of the neuroprotective approaches he mentioned in a study of reasonable size and duration.
However, he said that as keys to success, a neuroprotective treatment for glaucoma should work as upstream as possible on an important pathway to glaucomatous damage. In addition, it should be administered locally and well tolerated.
“Patients who do not yet have symptoms from glaucoma are not likely to use any treatment that has bothersome side effects,” Dr. Quigley said.
Discussing why IOP-lowering will continue to be a component of glaucoma management, Christopher A. Girkin, MD, MSPH, explained the reasons in terms of the fact that glaucoma is primarily an axonal disease that is localized to the lamina cribrosa and referring to the biomechanical model of glaucoma that implicates structural failure and strain in optic nerve head connective tissue in the pathogenesis of axonal injury.
“IOP is the stress or loading force in the biomechanical model, and so it is a critical determinant of laminar tissue strain,” said Dr. Girkin, professor and chairman, Department of Ophthalmology, University of Alabama at Birmingham (UAB). “We can’t get away from the effects of IOP on RGC injury, and that is why we will always be treating glaucoma by lowering IOP.”
Dr. Girkin, who is also director of the UAB Glaucoma Service and Optic Nerve Imaging Center, noted that because glaucoma is a disease of axogenic injury versus cell body injury, there is a window of opportunity for using neuroprotective and neuroregenerative strategies.
Nevertheless, treatment that addresses the pathologic process occurring within the lamina is still needed. Otherwise, as the lamina continues to remodel, there will be a live cell body in the retina with no connection to the brain.
Discussing the biomechanical model of glaucoma, Dr. Girkin explained that any mechanical model is built on two factors-stress and strain. In the biomechanical model of glaucoma, IOP acts as a source of stress on the sclera causing strain in the connective tissues of the scleral canal wall, lamina cribrosa, and peripapillary sclera that ultimately leads to axonal injury.
However, strain, which is the tissue response to stress, is also determined by tissue morphology (shape) and its material properties.
Dr. Girkin used the analogy of a road bridge to explain these concepts. In constructing a bridge, engineers design its shape and select materials so that the structure can withstand the stress caused by cars driving over it.
“In the eye, however, we can control neither the morphology nor the material properties of the lamina,” he said.
“All we can do right now is lower the stress by lowering the IOP, which means IOP will continue to be relevant in the treatment of glaucoma.”
Dr. Girkin noted, however, that a bridge can also collapse under its own weight if its morphological and/or material properties do not provide adequate structural support. The idea that the same situation is relevant to glaucoma pathophysiology is supported by the clinical observations that the disease can develop in patients with statistically normal IOP and progresses in some patients despite treatment that effectively lowers IOP.
Support for the validity of the biomechanical model of glaucoma also derives from the fact that in addition to IOP, the role of all known risk factors for glaucoma can be explained within the context of the model.
For example, pseudoexfoliation could potentially affect the material properties of the relevant connective tissues along with IOP. Corneal thickness-while directly related to the measurement of IOP-may also have a secondary biomechanical relationship.
“Perhaps corneal thickness is a biomarker for some material property or structural difference within the optic nerve,” Dr. Girkin said.
Furthermore, differences in optic nerve morphology that predict progression have an obvious relationship to optic nerve biomechanical responses. Even disc hemorrhages-classically seen as evidence for a non-mechanical mechanism-could be explained due to remolding of the laminar beam with resulting capillary disruption due to a purely mechanical insult.
Aging and diabetes result in advanced glycosylation end products that can change the material properties of the sclera and thereby affect the biomechanical behavior of the sclera and optic nerve. Regarding age and African-American ancestry, there is evidence that both of those demographic features can directly impact the material properties of the optic nerve head connective tissues.
“Drs. Crawford Downs and Massimo Fazio from our ocular biomechanics group found significantly less stress-induced strain in the sclera of eyes from donors of European ancestry compared with African Americans,” Dr. Girkin said. “We also know there are well-described racial differences in optic nerve head structure, and those may have direct biomechanical relevance.”
In the end, the biomechanical model of glaucoma takes into account that the optic nerve is a living mechanical structure and incorporates not only mechanical pathogenic mechanism, but also vascular, neurodegenerative, immunologic and cellular remodeling mechanisms in a complex interplay that are difficult to separate from each other, he concluded.
Christopher A. Girkin, MD, MSPH
Harry A. Quigley, MD
This article was adapted from presentations given by Dr. Girkin and Dr. Quigley during the 2015 meeting of the American Glaucoma Society. Dr. Girkin and Dr. Quigley have no financial interests to disclose that are relevant to the subject matter of their presentations.