Neuroprotective strategies for glaucoma therapy have been investigated extensively over the last few years with disappointing clinical trial results. However a significant proportion of patients with glaucoma still progress despite optimal intraocular pressure control. We have genetic information obtained from patients with advanced glaucoma via the Australian and New Zealand Registry of Advanced Glaucoma (ANZRAG). Candidate genes for rapid glaucoma progression are in the process of being identified in addition to those already found via this study. Biochemical pathways implicated by these glaucoma susceptibility genes identified from within the broad clinical context have the capability to be modulated for the development of neuroprotective agents which would then have the most potential to impact on human disease pathogenesis. Identifying pathways that already have clear clinical relevance increases the chances of finding a suitable neuroprotective therapy. We have developed an organotypic ex vivo rodent retinal explant model as a tool to rapidly screen potential neuroprotective agents identified from the clinical genetic studies for efficacy. This model also allows for exploration of the underlying molecular pathways modulated by such agents. Using this technique we will not only be able to describe the clinical relevance of the genetic abnormalities associated with patients known to have severe and advanced glaucoma but target specifically the biochemical defect with the potential to apply that directly back to the patient.
This project involves collaboration with colleagues at Flinders University and the University of Iowa. Candidate biochemical pathways for neuroprotection identified via ANZRAG will be examined for potential sites of modulation. Any potential sites able to be modulated by existing FDA approved medications will be prioritised for trial for neuroprotective efficacy via a retinal explant model which is a well described technique for examining mechanisms of neuroprotection. The preference would be for testing water soluble compounds as they are most likely to penetrate the cornea as an eye drop preparation without the risk of systemic side effects or the risk of endophthalmitis from an intravitreal injection. The molecular basis of the mechanism behind any neuroprotective efficacy discovered will be examined via techniques such as real time PCR and Western blot. The turnaround time for each experiment to determine a neuroprotective effect is approximately 2 weeks in total, meaning large numbers of compounds can be screened in this manner. The advantage of the current approach however is that despite the capability for reasonable experimental throughput, the screening process is targeted with proven clinical relevance being the priority.
Westmead Millenium Institute in Sydney has the resources and expertise for such studies including animal housing, confocal microscopy, real time PCR and Western blotting. Likewise, ANZRAG is an established study with its own infrastructure and resources. Many of the patients recruited via ANZRAG are relatively young. A combination of clinical and laboratory based research outlined in this study design raises the prospect of utilising any identified clinical agent in clinical trial on the same patient from which the original information came as a basis for personalised therapy in the future.
The opportunity ID for this research opportunity is 1827