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Ocular Tissue Engineering

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Ocular Tissue Engineering

Doctor Fred Chen is a Senior Lecturer at the University of Western Australia and he established the Ocular Tissue Engineering Laboratory at Lion Eye Institute in 2010. Fred has gained international recognition in the field of retinal clinical trials endpoint analysis, retinal pigment epithelium (RPE) transplantation and stem cells. Through his doctoral
thesis (http://discovery.ucl.ac.uk/1318070/), “RPE transplantation in retinal diseases”, he has developed and validated new methods of analyzing functional and anatomical outcomes of clinical retinal cell therapy. This work has led to the first phase I trial of RPE sheet transplantation in the UK.

His group is currently exploring autologous cell sources for retinal preservation and regeneration, and new methods of deriving induced pluripotent stem cells for retinal differentiation. In parallel with his stem cell work, Fred’s group also conducts clinical research to validate new diagnostic retinal imaging tools and develop software to measure disease progression in macular degeneration and retinal dystrophy. He is a principle investigator for several observational studies in visual acuity and microperimetry reliability, long-term outcomes of anti-VEGF therapy, blindness rate in Western Australia, early detection of toxic retinopathy and phenotype-genotype correlations in macular degenerations and inherited retinal diseases (http://irdregister.org.au/). He is also the lead investigator for novel laser and new drug treatments for drusen, geographic atrophy and neovascular macular degeneration.

His collaborators include Murdoch University, Edith Cowan University, Curtin University, Ear Science Institute Australia, Queensland Eye Institute, Queensland University of Technology, Flinders University, Save Sight Institute, University of Sydney, Centre for Eye Research Australia, University of Melbourne, Moorfields Eye Hospital and University College of London.

Research Projects

Aim: To examine the repeatability and comparability of 2 visual field instruments (microperimeters): the Nidek MP1S and the Centrevue MAIA microperimeters, which use the latest imaging technology to simultaneously test the function of the retina and track retinal image motion due to eye movement. As new regenerative medicine and neuro-protective treatments for macular degeneration are emerging, these microperimeters are becoming more important in the monitoring of disease progression and response to therapy. The result from this study will be critical for future studies using microperimetry and design of clinical trials which use microperimetry as outcome measures.

Aim: To examine the changes in vision in patients with retinal degeneration. We know that patients with retinal degeneration often have stable visual acuity for many decades. However, they notice progressive patchy loss of paracentral vision that can’t be measured by conventional visual acuity test. We want to document the gradual decline in paracentral vision over a period of 12 months in patients with dry retinal degeneration. This study will involve specialised visual field testing using a new microperimeter called the Nidek MP1S. In addition to microperimetry, these patients will undergo detailed reading tests, questionnaires and retinal imaging for correlation. The results from this study will be used for planning large clinical trials looking at efficacy of neuroprotective agents and cell transplantation in preventing degeneration of the macula.

The human corneoscleral limbus contains multipotent stem cells that can be isolated and cultured for clinical applications, such as the treatment of limbal stem cell deficiency. Studies in rodents have shown that stem cells in the limbus can be induced to form floating neurospheres in the presence of the BMP receptor antagonist Noggin and that these neurospheres can be further dedifferentiated to pluripotency using conditioned media. Limbal neurospheres (LiNS) express three (SOX2, KLF4 and C-MYC) of the four transcription factors identified as being sufficient for reprogramming cells to pluripotency, lacking only Oct4, the master pluripotency gene. The induction of Oct-4 expression in rodent LiNS by microenvironmental signals suggests close similarities between the LiNS transcriptome and that of pluripotent stem cells. Although results from our lab and others have described the induction of LiNS from human limbal tissue, the induction of pluripotency from primary human LiNS has not yet been reported. Our project aims to examine the effects of microenvironmental factors on pluripotent gene expression in human LiNS.

Since the development of the induced-pluripotent-stem (iPS) stem cell reprogramming technique by Yamanaka in 2006, the field of cellular reprogramming has progressed rapidly and the principle of using exogenous transcription factors to control cell fate has been widely studied in the context of inducing pluripotency. Recent developments, such as the replacement of retroviral transgene delivery with the use of synthetic mRNA to achieve reprogramming factor expression, have begun to address the technical obstacles that remain between the new method and its implementation in a clinical setting. The primary aim of this project is the production of retinal pigment epithelium (RPE) using exogenous transcription factors delivered as synthetic mRNA. RPE dysfunction is a major contributor to retinal disease, including age-related macular disease, and transplantation of healthy RPE has been shown to improve visual function in human patients. RPE patches are currently being developed using human embryonic stem (hES) cell cultures, however, immunological and ethical concerns limit the suitability of these cells for clinical application. To address these concerns, this project aims to evaluate a number of donor cell populations for reprogramming potential, including umbilical cord blood, towards the end of identifying the most suitable cells for tissue engineering applications.

Dry age-related macular degeneration (AMD) is one of the most common causes of irreversible blindness. Unlike the wet form of AMD, the dry form of AMD can progress very slowly and it can impair reading ability for many years before it is detected. Research at Lions Eye Institute is being conducted into exploring the risk factors for dry AMD, characterising different types of dry AMD, clinical trials of novel drug treatment and the potential of cell replacement therapy.Macula is a specialised area of the light sensing retina that serves central vision, allowing us to read, see people’s faces and drive a car. As dry AMD develops, many people will require greater contrast in the text they read and brighter light to see objects clearly at night. Some will notice distortion and blur patches of vision in the centre causing “letters on the page to jump around”. One eye is often affected more severely than the other and hence many people will ignore these symptoms of early dry AMD until the better seeing-eye is losing sight.

Several risk factors for development of dry AMD have been proposed including smoking and family history. Research has shown specific formulation of vitamins and minerals may be beneficial in retarding progression of high risk early AMD to late stage AMD. However, use of these supplements should be discussed with a retinal specialist who can distinguish high risk early AMD from other macular diseases such as pattern dystrophy or central serous retinopathy that can often be confused with the common type of AMD. Experimental laser treatment are also being investigated and Lions Eye Institute is currently part of a multi-centre multi-national study examining nanosecond laser inducing regression of early stage of AMD. It is thought that these lasers stimulate removal of debris within the retina and reverse subtle age-related impairment of the vision.

Evolution of early stage into late dry form of AMD occurs over many years or decades. Lions Eye Institute is examining features in the patient or in the eye that may predict patients who are likely to progress faster than others. We know that are specific genetic profile and features within the eye that can only be seeing using specialised retinal camera that can predict progression rate.

Researches in the most appropriate interpretation of these images are amongst the top priorities for the Imaging Group at the Lions Eye Institute. We have acquired several state-of-the art retinal cameras and recruited experts in imaging analysis to set up an Imaging Group to facilitate our investigation into risk profiling of patients with dry AMD.

Once retinal cells become damaged in dry AMD, novel treatment targeting inflammatory and cell survival signal pathways in the eye are being investigated in multi-centre and multi-national clinical trials to arrest further progression. Several clinical trials are starting to recruit patients with geographic atrophy, a specific type of dry AMD where extensive cell damaged has occurred in the macula. Being part of these clinical trials will enable patients to contribute to the development of new drugs and monitored closely even if they do not receive the active medication during the trial. Lions Eye Institute has actively engaged with pharmaceutical companies to bring to Perth the opportunities for Western Australians to participate in these clinical trials with the potential for patients to receive new treatment for dry AMD.

Stem cell therapy has the potential to prevent further vision loss as well as restoring vision in people blinded by dry AMD. The Tissue Engineering Laboratory at the Lions Eye Institute is actively developing tissue replacement to reconstruct damaged macula with retinal cells grown from the patient’s own cells. This autologous stem cell transplantation approach is a long term project and many years of development is anticipated before it can be tested in human subjects.

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