Future Strategies for Glaucoma Management

Dr. Andrew White

Glaucoma is the leading cause of irreversible blindness in the world with over 70 million affected. Scandinavian studies have identified that the lifetime risk of bilateral blindness from glaucoma is about 15 per cent and roughly another 30 per cent are blind in one eye.

Sadly, despite some very exciting advances in stem cell technology, including the recent advances in stem cell transplantation in the retina undertaken at the University of Oxford and the ability to ‘print’ a retina from stem cells recently developed at the University of Cambridge, we are still a very long way from being able to reverse vision loss from glaucoma. This means, for the time being we must focus our efforts on halting glaucoma progression so patients do not have significant vision loss in their lifetime.

Developing strategies to control intraocular pressure (IOP) is only part of the modern day glaucoma management story because a significant proportion of people with glaucoma progress despite optimal IOP control. Furthermore, between 50–90 per cent (depending on the population) of people with open angle glaucoma have an IOP in the normal range. Despite that, IOP control is still the only really proven strategy for slowing or halting glaucoma progression.

…today the thinking is more to do with accelerated ageing of the optic nerve than
just high IOP

Work being undertaken by local clinician-ophthalmologists may add further weapons to the treatment armoury for this eye disease. One of the main areas of glaucoma research in this field relates to finding potential drug treatments that halt progression of vision loss by means other than controlling intraocular pressure. There have been trials in the past on new compounds developed specifically for this but none have successfully completed clinical trial. There have been some notable very expensive failures. The time and expense of developing new compounds means there is less enthusiasm for this approach.

The focus has now shifted to examining compounds that have already undergone the clinical approval process which may have a previously undiscovered role in the treatment of glaucoma. Australian clinician-scientist ophthalmologists are playing a leading role in this research.

Neuroprotection
The thinking behind what glaucoma actually is has changed – today the thinking is more to do with accelerated ageing of the optic nerve than just high IOP. Looking at ways to stop this ageing is called neuroprotection.

Based on my work undertaken at the University of Cambridge UK, I have been examining the mechanisms behind the neuroprotective effect of a common class of blood pressure medications called angiotensin II blockers. There is some evidence that this neuroprotective effect is mediated by the ability of angiotensin II blockers to reduce intracellular free radical formation that can lead to cellular apoptosis (cell death) which is accelerated ageing. This may be independent of its blood pressure control effects. The Renin-Angiotensin System is a vital part of the body’s homeostatic mechanisms and there is increasing evidence of its importance in the eye. Defects in its regulation are implicated in many eye diseases including glaucoma. By understanding how this class of drugs can protect dying cells of the optic nerve via this pathway we may be able to develop better treatment strategies to halt glaucoma progression. This may involve local application of a derivative of this class of drugs or recommending systemic therapy – especially if the patient already requires treatment for hypertension.

A relevant clinical question is whether ophthalmologists should play a role in recommending appropriate blood pressure medications to patients’ GPs. There had been previous evidence that calcium channel blockers also had a role in preventing glaucoma progression but clinical evidence for this has not been consistent. The clinical evidence for a change in blood pressure medication because of a glaucoma diagnosis may not be warranted at present, but this may change in the future. This work now continues at the University of Sydney.

Research: Professor Stuart Graham

Insight: BDNF and TrkB Signalling in Optic Neuropathy

Professor Stuart Graham from Macquarie University also has an interest in neuroprotection. Currently, there are several different strategies to try to protect the optic nerve and retinal ganglion cells in glaucoma. These include either slowing or blocking the cell death pathways, or stimulating cell survival pathways. Professor Graham and his team have explored the latter with an attempt to stimulate the pathway which involves Brain Derived Neurotrophic Factor (BDNF). This is one of many stem cell derived growth factors found in the body and it is thought that it may have one of the strongest protective effects against cell death. His team has established the importance of this pathway in a rodent model of glaucoma which showed that lack of BDNF signalling was associated with reduced visual function, and that a naturally occurring flavonoid (7,8-DHF) found in many vegetables could stimulate the pathway and lead to greater protection of the visual pathway in the experimental glaucoma model.

It is not clear as yet whether changes in diet would likely be more effective than a concentrated supplement. There is ongoing work to explore this and further compounds to determine whether these could be safely administered to patients and have relevance to human glaucoma. As research continues, it may lead to clinical trial of these compounds in the near future.

Researcher :Professor Robert Casson

Insight: Metabolic Neuroprotection

Research by Professor Robert Casson from the University of Adelaide has focussed on the concept of ‘bioenergetic neuroprotection’.

Currently, the only method of neuroprotection is to lower the pressure in the eye, either with drops, laser or surgery. There is, however, ample evidence indicating that insufficient energy supply is part of the problem in glaucoma; hence, energy delivery may be part of the solution. The pathogenesis of glaucoma remains unclear, but there is considerable evidence that inadequate blood supply to the optic nerve head is involved. It has recently been shown that delivery of glucose to the eye can temporarily recover vision in patients with severe glaucoma. Professor Casson’s group has previously shown that elevated vitreous glucose levels provide robust neuroprotection against experimental ischemic retinal injury and experimental glaucomatous optic nerve neurodegeneration.

Recently, they showed that topical application of glucose reached the vitreous cavity in pseudophakic individuals, and that a visual psychophysical parameter – contrast sensitivity – temporarily recovered in pseudophakic individuals with severe POAG after topical glucose application.

The method of topical application has raised concerns that the beneficial visual effect may have been due to optical changes to the cornea rather than bioenergetic neurorecovery in the retina. To address this concern, the group conducted a double-blind, crossover, follow-up study, and re-recruited seven eyes of five subjects from the previous topical trial and altered the delivery method of the glucose (trial registered as ACTRN12612001134819). Subjects received either 0.3 ml of 50 per cent glucose subconjunctivally (delivered into the inferior fornix) or osmotically-matched saline, then vice versa after a two to three week ‘wash-out’ period.

Based on previous data, a change in contrast sensitivity after two hours was the primary outcome. The mean contrast sensitivity improved or was unchanged at all measured spatial frequencies in all subjects. Despite the small sample, the primary outcome was highly significant: 0.24 log units greater than baseline at 12 cycles/degree testing (95 per cent confidence interval 0.12 – 0.36; P < 0.001). There is no suggestion that regular large doses of glucose should be given to protect the optic nerve in patients at risk. However, the present findings support the notion that energy insufficiency is part of the pathogenesis of POAG, in at least some patients, and motivate further bioenergetic-based research in glaucoma and other optic nerve and retinal diseases.

Researcher: Professor Jonathan Crowston

Although there is substantially increased knowledge of the diverse processes that can damage the optic nerve in glaucoma, there is less knowledge about how lifestyle impacts on optic nerve vulnerability to glaucoma damage. Professor Jonathan Crowston and his team at the University of Melbourne have developed an optic nerve stress test that is used in laboratory experiments to monitor the recovery of the optic nerve after a challenge induced by elevating eye pressure. It has been previously demonstrated that older laboratory mice are less able to recover from an elevated eye pressure challenge than young mice. This suggests that accumulating age renders the optic nerve more vulnerable to injury. Subsequent work has shown this negative impact of ageing can be reversed by exposing mice to daily exercise in an effort to manipulate mouse feeding behaviour. Environmental or lifestyle factors, therefore, appear to be able to improve optic nerve recovery after ageing.

In a final set of experiments, Dr. Vicki Chryostomou the University of Melbourne laboratory has also shown the ability of young mice to recover after optic nerve injury can be impaired. By feeding young mice an unhealthy high fat diet she found the opposite effect – that a high fat diet impairs optic nerve recovery to the extent that young mice respond to an eye pressure injury as poorly as older mice. These experiments raise the intriguing possibility that lifestyle choices might impact optic nerve resistance to injury and pave the way for future clinical studies to determine whether lifestyle choices also impact glaucoma progression in humans.

Researcher: A/Prof Jamie Craig

Despite the fact that we know that having an affected sibling with glaucoma increases the risk of developing glaucoma by up to 9–10 times, the number of genes directly implicated in the pathogenesis of glaucoma is disappointingly small and most relevant to specific subtypes of glaucoma which form the minority of the burden of disease. This may reflect the complexity of the disease process where more than one part of the cell survival pathway is dysfunctional leading to glaucoma.

Over several years, Prof Craig and his team based at Flinders University have been developing a large collection of genetic samples of people with advanced glaucoma as part of the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Any patient can be referred to this registry by a health practitioner via the registry website www.anzrag.com/ for testing of the common genetic defects implicated in advanced glaucoma. The samples are stored for testing of potential new genetic loci implicated in glaucoma. This approach has led to the identification of several new candidate genes by what is known as Genome Wide Association Studies (GWAS). Prof. Craig’s team was the first in the world to identify these new genes, though these results have now been replicated and validated in other sites around the world. At present, it is not clear what these genes actually do or how they may be modulated to halt glaucoma progression. Untangling the complexity of metabolic and cell survival/cell death pathways will take time. More genes are likely to be found over time. The work continues and we can expect more exciting results from this team.

Researcher: Dr. Alex Hewitt

Drs. Alex Hewitt, Alice Pébay and Raymond Wong from the University of Melbourne are working on a very novel technology related to how to model glaucoma in cell culture. This research may answer some of the questions posed by the work of Prof. Craig.

The extreme difficulty in obtaining ocular tissue from living people currently represents a major barrier to the development of new treatments for glaucoma. Recent breakthroughs in stem cell technology have led to the ability to generate stem cells from adult tissue, and these ‘induced pluripotent stem cells’ now represent a powerful disease modelling tool (and are less ethically contentious than embryonic stem cells). Generating induced pluripotent stem cells directly from patients allows cells to be differentiated into specific cells of interest for disease modelling, drug screening, and understanding of fundamental pathogenic mechanisms. It is envisaged that appropriate cellular systems will be developed in future years that will enable researchers to study and ameliorate the pathogenic consequences of retinal ganglion cell apoptosis. This could lead to the identification of genetic defects implicated in glaucoma found in patient screening studies such as ANZRAG. These defects could then be tested for the ability to be modulated by drug therapy, in vivo, before being taken back to the patient in clinical trial.

Conclusion

It is exciting to see that so much cutting edge glaucoma research focussed on developing new therapies and management strategies is based in Australia. Many of the research projects I have written about here were presented at a symposium I co-chaired with Professor Kuldev Singh from Stanford University at the 45^th RANZCO conference in November 2013, and they all generated enthusiastic discussion. As all of these researchers are clinical ophthalmologists as well, they are well placed to translate their ground-breaking research into practice. Ultimately one or all of them may become the basis for a change in the treatment paradigm of glaucoma.

We can only wait in hope.

Dr. Andrew White B.Med.Sci(hons) MBBS PhD FRANZCO is a glaucoma specialist at Westmead Hospital and Chair of the Expert Advisory Panel at Glaucoma Australia. Dr. White’s subspecialty interest is glaucoma and his research interests are diverse, encompassing neuroprotection, pathological changes associated with selective laser trabeculoplasty and a number of clinical trials as well as a study looking at the genetic basis of advanced glaucoma. He has been invited to speak at glaucoma and ophthalmology conferences in the UK, Europe, Asia and Australasia.