Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
Please could you give a brief introduction to glaucoma?
Glaucoma is normally caused by increased pressure of aqueous humour fluid in the eye. A defining feature of this disease is destruction of a particular type of cells in the retina called retinal ganglion cells and excavation of the optic disc region.
It can best be termed as a "silent thief of sight" because the loss of vision often occurs gradually over a long period of time, and symptoms can only be detected when the disease is already advanced. Once lost, vision cannot be recovered and so treatment is aimed at preventing further loss.
Worldwide, after cataracts, World Health Organisation (WHO) recognises glaucoma as the second leading cause of blindness. It affects one in 200 people aged fifty and younger, and one in 10 over the age of eighty.
If the condition is detected early enough, it is possible to arrest or slow its progression with medical and surgical means.
Due to increasing aging populations, numbers are increasing steadily in the developed countries. This poses a major challenge to future healthcare planners.
What was previously known about the mechanism underlying glaucoma?
Increased intraocular pressure (above 21 mmHg) is the most important observation and the only modifiable risk factor for glaucoma. However, some patients may have high eye pressure for years and never develop damage, while others can develop retinal damage at a relatively low pressure.
It is widely believed that excitotoxicity and associated oxidative stress play an important role in the retinal ganglion cell loss. Changes in vascular flow and neurodegenerative theories are being proposed more recently. Neurotropic factors released by the neuronal and glial cells in the retina are critical for the survival of retinal ganglion cells.
The production of one such factor called Brain Derived Neurotrophic factor (BDNF) is decreased in the retina in glaucoma. This leads to deactivation of the BDNF specific Tropomyosin related kinase B (TrkB) receptors on the cell membrane of these cells. As TrkB receptors promote cellular survival, downregulation of their activity eventually leads to retinal ganglion cell loss.
What has your recent research shown?
A novel phosphatase called Shp2 regulates the activity of the TrkB receptors in the retinal ganglion cells in glaucoma. Shp2 is normally involved in cell growth and differentiation but adopts a completely different role in glaucoma.
We found that Shp2 binding to TrkB receptors is dependent on another protein caveolin. In glaucoma, caveolin recruits both TrkB and Shp2 and brings them in close proximity to each other. Shp2 then acts upon the TrkB receptor leading to its deactivation ultimately leading to cell death.
How did your research originate?
Irreversible retinal ganglion cell loss is a major pathology associated with glaucoma, yet the mechanisms for this injury are not understood. It is extremely important to understand the basic neurodegenerative mechanisms in glaucoma for the development of neuroprotective strategies.
Recent research has shown that TrkB gene therapy and BDNF administration can protect the retinal ganglion cell loss. Sadly, the protective effects of exogenously administered BDNF are transient and do not translate into enhanced retinal ganglion cell survival for long.
The mechanism underlying this change in sensitivity to BDNF is poorly understood and has perplexed scientists for a long time. Our investigations originated from the hypothesis that there could be a simultaneous deactivation of the TrkB receptors by a partner phosphatase which suppresses the effects of BDNF.
What impact do you think your research will have on glaucoma treatment?
This study provides a better understanding of why and how the retinal ganglion cells degenerate and equips us to better design effective therapeutic strategies to prevent or at least delay the onset of retinal ganglion cell loss in glaucoma patients.
It also explains why existing neuroprotective treatments to prevent retinal ganglion cell loss fail in the longer term and suggests alternative strategies to limit this failure.
This research identifies important signalling pathways that are associated with retinal ganglion cell loss in glaucoma. A novel treatment would be to specifically inhibit Shp2 phosphatase using the synthetic inhibitors or knockdown technology.
In any case, our research reinforces the idea of using neuroprotective strategies in conjunction with the conventional intraocular pressure lowering therapies to protect the retina in glaucoma patients.
Do you think your research will have an impact on any other conditions?
This research elucidates the role of neurotrophic factors in retinal ganglion cells and provides an opportunity to exploit key points in the signal transduction to develop neuroprotective strategies for therapeutic interference. We learn what role Shp2 and caveolin proteins play in preserving the normal cell structure and function in general and their role in regulating TrkB receptor signalling in particular.
The results may be useful to treat other optic neuropathies e.g., ischaemic optic neuropathy and optic neuritis in multiple sclerosis and may be extrapolated to other neurodegenerative disorders of the brain including Alzheimer’s and Parkinson’s disease.
What plans do you have for further research into this field?
Clinical trials to administer BDNF have been disappointingly negative, because of its poor delivery, short half-life and poor pharmacokinetic profile.
BDNF also possesses a broad spectrum of physiological activities, and changes in its levels can imbalance other neurological processes, which unfortunately acts as a limitation for therapeutic applications. No suitable exogenous agent was identified till late, that could act as a robust TrkB agonist.
We are investigating novel compounds which can act as specific TrkB receptor agonists. These compounds will be devoid of any side effects associated with the BDNF administration.
We are also trying to specifically inhibit the Shp2 in vivo. Collectively, this two pronged approach will help to prevent the degeneration of the retinal ganglion cells in glaucoma.
How do you think the understanding of the mechanisms underlying glaucoma will develop?
Presently, the greatest hurdle in the field of glaucoma research is the availability of suitable animal models representing the disease. It is important to have an appropriate animal model which undergoes slow retinal degeneration in response to increased intra-ocular pressure.
Besides, most of the research is currently focused on identifying new genes involved in the glaucoma pathogenesis which is a welcome trend, but more mechanistic insights can be obtained only by studying changes at the protein level, like post-translational changes which very well go below the radar of current methods to detect changes at the gene level. These subtle differences can be measured using highly sensitive proteomics techniques.
How do you think the future of treatment of glaucoma will progress?
Glaucoma currently affects >70 million people and approximately 7-million are blinded by this devastating disease worldwide.
Given the multidimensional nature of glaucoma pathology, it is important that more emphasis is placed on the neuroprotective strategies to treat the retina, the optic nerve and higher visual centers in the brain. Any changes in the vascular flow or permeability of the retinal blood vessels too can have critical effects on the retina in this disease.
The retina needs to be scanned regularly for any changes in the architecture or vasculature. The future treatment regimens should definitely involve the use of neuroprotective drugs to protect the degenerating retina.
Would you like to make any further comments?
Glaucoma is affecting mankind in gigantic proportions. I would emphasize, that several fold more funding is required to make significant progress and control this ocular disorder.
New research across the globe shows that it is a multifactorial disease and has similarities to other neurodegenerative disorders affecting the brain like Alzheimer’s and Parkinson’s disease.
It is the merging of the different cascade of pathological events like depleting support of the neurotrophic factors, aggregation of the toxic amyloid β fragments, uncontrolled proteolytic activity coupled with the insult rendered by increased intra-ocular pressure that promotes the degenerative changes in the retinal ganglion cells and optic nerve head.
Finally, I thank Prof. Stuart Graham whose intellectual inputs were essential to unravel this mystery associated with the retinal ganglion cell degeneration in glaucoma.
Where can readers find more information?
Readers can find more information at:
About Dr. Vivek Gupta
Dr. Vivek Gupta is a scientist at the Australian school of Advanced Medicine, at Macquarie University.
He received B.Sc. in 1997 followed by a Master’s degree in biochemistry in 2002. He completed PhD in the field of Protein chemistry and technology in 2008, identifying the mechanisms of action of alpha-1-antitrypsin. He discovered that heparin binding leads to activation of alpha-1-antitrypsin inhibitor several fold.
He joined University of Geneva in 2008 and continued his research in the field of microbiology and molecular medicine. He moved to the prestigious Dean A. McGee Eye Research Institute at the University of Oklahoma and elucidated the complexities associated with the mechanisms of phototransduction and retinal neuroprotection.
In 2010, he was able to report how the cyclic nucleotide gated channels in the retina are regulated under different physiological conditions. He also elucidated the mechanistic complexities of some of the important cellular signalling pathways in the retina.
With a rich expertise in the fields of protein chemistry, cellular and molecular biology, and visual electrophysiology he has been at the forefront of research into the causes of retinal and optic nerve degeneration in glaucoma and other optic neuropathies. Presently, at Macquarie University in Sydney, he is investigating various neuroprotective molecules to protect the retina ganglion cells in glaucoma.
He has received several awards and fellowships in recognition of his research. He also serves on the editorial boards of several scientific journals. He is actively involved in the community outreach programmes educating people about glaucoma and the need for regular eye check-ups.