MULTI-CENTRED CLINICAL EVALUATION OF A NOVEL KERATOPROSTHESIS
Funder
National Health and Medical Research Council
Funding Amount
$515,091.00
Summary
The prosthesis developed by applicants, known also as Chirila keratoprosthesis, is an artificial implantable device designed to replace a diseased cornea or a failed corneal graft, and can be used in patients with no hope for a conventional replacement of the cornea with donor tissue. The device may ultimately find a wider application, as it has the potential to give better visual results than human donor grafts. Even when not rejected, the donor grafts may lead to problematic healing patterns a ....The prosthesis developed by applicants, known also as Chirila keratoprosthesis, is an artificial implantable device designed to replace a diseased cornea or a failed corneal graft, and can be used in patients with no hope for a conventional replacement of the cornea with donor tissue. The device may ultimately find a wider application, as it has the potential to give better visual results than human donor grafts. Even when not rejected, the donor grafts may lead to problematic healing patterns and astigmatism, both limiting the final vision of patients. From the 45 million blind people worldwide, at least 10 million are due to corneal diseases or trauma. The figures released by WHO suggest a doubling of this number by year 2020. Many countries are unable to provide sufficient donor corneas, sometimes for cultural-religious reasons. In developed countries, the replacement with donor tissue is a common procedure, but many patients remain untreated because their prognosis for successful grafting is poor. Figures released in Australia show that long-term success of donor transplantation is unlikely in the patients identified as high-risk recipients. Furthermore, even technically successful cases show disppointing final vision. The significance of the applicants' artificial cornea is that allows high-risk, or otherwise untreatable corneal blind patients, to have their vision restored, and it could ultimately reduce the need for donor corneal tissue. A phase I pilot study has been completed, and Phase II is currently underway with support from NH and MRC. These studies showed that the Chirila KPro is an effective means of reversible replacement of a diseased cornea.The proposed Phase III will evaluate both safety and effectiveness in different categories of patients in comparison with published outcomes of donor grafting, and will establish unequivocally the clinical potential of this prosthesis.Read moreRead less
Analysis Of FGF Receptor Signalling Involved In Lens Cell Proliferation And Differentiation
Funder
National Health and Medical Research Council
Funding Amount
$343,028.00
Summary
Cataract, the loss of transparency of the eye lens, is the leading cause of blindness in the world. An eventual cure for cataract depends on a better understanding of the basic molecular processes in the normal and cataractous lens. Our research has focussed on identifying the molecules that control the formation and maintenance of the lens. Growth factors are important regulators of cell behaviour and our studies have provided compelling evidence that members of the FGF growth factor family pla ....Cataract, the loss of transparency of the eye lens, is the leading cause of blindness in the world. An eventual cure for cataract depends on a better understanding of the basic molecular processes in the normal and cataractous lens. Our research has focussed on identifying the molecules that control the formation and maintenance of the lens. Growth factors are important regulators of cell behaviour and our studies have provided compelling evidence that members of the FGF growth factor family play pivotal roles in lens developmental biology by influencing lens cell proliferation and differentiation. An important finding from our laboratory is that FGF induces lens epithelial cell proliferation and differentiation at different concentrations. The FGFs elicit intracellular responses upon binding to and activating cell surface FGF receptors (FGFRs). The FGFRs are membrane bound tyrosine kinases which upon activation, activate specific signalling pathways leading to a specific cellular response. To understand how FGFs mediate and regulate different responses in lens cells, namely cell proliferation and fibre differentiation, we plan to examine the role of FGFRs in normal lens development using genetically altered FGFRs that will be expressed specifically in lenses of transgenic mice. While it is known that four different FGF receptor genes are expressed by the normal developing lens, it is unknown what role each of these play in the process of lens cell proliferation and differentiation. In addition, as we can reproduce a specific FGF-induced lens cellular response in vitro, we will use our lens explant culture system to dissect the signalling pathway(s) downstream from specific receptor activation and correlate this with a specific cellular response. By identifying the molecules and mechanisms that control the cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.Read moreRead less
Functional Recovery From Retinal Degeneration: Genetic, Environmental And Senescent Models
Funder
National Health and Medical Research Council
Funding Amount
$265,888.00
Summary
This project is directed towards treatment for the blindness caused by retinal degeneration. The retina of the eye degenerates in several groups of diseases, and from several causes. Many cases affect young people and result from small genetic mutations in key proteins. Many appear to be caused by environmental damage to the retina, perhaps at birth. Retinal degeneration causes progressive blindness in a minority of younger people (about 1 in 4,000, so 5,000 Australians and 1-2 million people wo ....This project is directed towards treatment for the blindness caused by retinal degeneration. The retina of the eye degenerates in several groups of diseases, and from several causes. Many cases affect young people and result from small genetic mutations in key proteins. Many appear to be caused by environmental damage to the retina, perhaps at birth. Retinal degeneration causes progressive blindness in a minority of younger people (about 1 in 4,000, so 5,000 Australians and 1-2 million people world-wide). This condition is known as Retinitis pigmentosa. However, the normal retinal undergoes a slow loss of photoreceptors whose effect is cumulative, so that the vision of all peoples slowly fades towards the blindness of old age. In this form, retinal degeneration affects potentially everyone. We have recently published an 'oxygen toxicity' theory of retinal degeneration to account for both retinitis pigmentosa and senescent degeneration. The theory applies whether the dystrophy is preciptated by genetic mutation or by environmental factors . By the time a person becomes aware of blindness (commonly night blindness) from retinal degeneration, the loss of vision results (it is argued) from 2 causes: the death of some photoreceptors (the retinal cells which detect light) and damage to surviving photoreceptors. Both death and damage are caused by oxygen toxicity, arising from particular features of the retina's metabolism and blood supply. Further, the relentless progression of the blindness is inherent in the mechanisms of oxygen toxicity. In preliminary work we have been able to slow retinal degenerations and, importantly, to restore function in degenerating retinas by countering the oxygen toxicity. Experiments are proposed to expand this evidence and explore the time course, permanence and generality of these effects. The tests of retinal recovery and stability, and the mechanisms of countering oxygen toxicity will be readily applicable to clinical trials.Read moreRead less
Studies Of Antigen Presenting Cells In The Anterior Segment Of The Eye And Their Role In Immune-mediated Ocular Disease
Funder
National Health and Medical Research Council
Funding Amount
$241,018.00
Summary
Dendritic cells (DC) are considered the 'sentinels' of the immune system because they are capable of trapping antigenic material derived from invading organisms such as bacteria and viruses in peripheral tissues-organs (skin, gut, respiratory tract etc) and then transporting these antigens to the lymphoid organs where they 'alert' the immune system to potential 'dangers' and elicit appropriate T cell responses. If the antigens are novel this mechanism forms the basis of primary cell-mediated imm ....Dendritic cells (DC) are considered the 'sentinels' of the immune system because they are capable of trapping antigenic material derived from invading organisms such as bacteria and viruses in peripheral tissues-organs (skin, gut, respiratory tract etc) and then transporting these antigens to the lymphoid organs where they 'alert' the immune system to potential 'dangers' and elicit appropriate T cell responses. If the antigens are novel this mechanism forms the basis of primary cell-mediated immune responses. Previously 'educated' T cells may upon contact with antigens in the periphery (when presented by other antigen presenting cells [APCs], such as macrophages) become activated. This forms the basis for secondary immune responses. Immune and inflammatory responses in the eye are held in check to avoid permanent damage to the delicate tissues and maintain visual function. The mechanisms which regulate immunological responses in the eye are only now becoming clear. Studies in the Chief Investigators laboratory over the last 7 years have been aimed at unravelling the life cycle and function of APCs in the eye. The present study has three specific aims: 1) Determining whether DC in the eye once they have taken up antigens migrate to the spleen or local lymph nodes? 2) The second aim of this project is to use an animal model of uveitis and transfer fluorescent labelled donor T cells to study the events in the living eye which lead to autoimmune uveoretinitis. In particular we wish to identify the cells that present antigen to infiltrating lymphocytes. 3) Patients often develop posterior uveitis (an autoimmune condition) after a cold or bacterial infection. We aim to mimic conditions of acute inflammation in the eye to see whether this may secondarily predispose the eye to attack by autoreactive lymphocytes.Read moreRead less
Uncovering The Aetiology Of Myopia Through Identification Of Refraction And Ocular Biometric Genes
Funder
National Health and Medical Research Council
Funding Amount
$697,786.00
Summary
Myopia or short-sightedness affects 1 in 4 people in the Western world and is a major source of uncorrected vision loss, as well as blindness. This proposal aims to identify genes in myopia using a new technique called genome wide association. We will apply this technique to individuals collected through a population based Eye study to allow us to identify these genes. The outcomes of this work will allow us to identify high risk individuals as well as develop new measures to prevent myopia.
Understanding The Genetic Determinants Of Central Corneal Thickness And Its Functional Role In Glaucoma Pathophysiology
Funder
National Health and Medical Research Council
Funding Amount
$297,263.00
Summary
Glaucoma is a common cause of blindness and visual diability in Australia. It is caused by a combination of environmental and genetic factors. People with a thin cornea (the clear covering at the front of the eye) are at increased risk of glaucoma. We are investigating the biological link between the cornea and glaucoma as well as identifying genes that determine corneal thickness. Some of these genes may also cause glaucoma. Understanding this will lead to better diagnosis and treatment.
The Functional Basis Of Direction Selectivity In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$376,320.00
Summary
Motion is an everday visual experience, and in this project we are attempting to explain how our brains are able to detect the direction in which an object is moving. Surprisingly this is first accomplished within the retina, the light-sensitive system of neurons at the back of the eye. Thus the eyes are able to tell the brain in which direction an object is moving. So the question becomes, how do the eyes do it? We know that there is a special class of neurons, the direction-selective ganglion ....Motion is an everday visual experience, and in this project we are attempting to explain how our brains are able to detect the direction in which an object is moving. Surprisingly this is first accomplished within the retina, the light-sensitive system of neurons at the back of the eye. Thus the eyes are able to tell the brain in which direction an object is moving. So the question becomes, how do the eyes do it? We know that there is a special class of neurons, the direction-selective ganglion cells, which are able to detect the direction of image motion. The activity of these cells is increased by excitatory connections and reduced by so-called inhibitory connections. This project aims to identify the neural origin of the inhibitory connections, and discover how the excitation and inhibition work together to compute the direction of motion.Read moreRead less
Genetic Determinants Of Inherited Optic Neuropathies
Funder
National Health and Medical Research Council
Funding Amount
$249,750.00
Summary
Glaucoma is a slowly progressive visual disorder of the optic nerves often but not always associated with elevated pressure in the eyes. There is a strong genetic component. It is estimated to affect in excess of 60 million people worldwide with more than 6 million of those blind in both eyes. It is the second commonest cause of visual impairment in the developed world, and is present in up to 10% of the population by age 90. Numbers of affected patients in Australia are expected to double in th ....Glaucoma is a slowly progressive visual disorder of the optic nerves often but not always associated with elevated pressure in the eyes. There is a strong genetic component. It is estimated to affect in excess of 60 million people worldwide with more than 6 million of those blind in both eyes. It is the second commonest cause of visual impairment in the developed world, and is present in up to 10% of the population by age 90. Numbers of affected patients in Australia are expected to double in the next 30 years. Current methods of early detection and treatment are often inadequate, and associated visual loss is irreversible. There is a strong need for greater understanding of the disease process and new strategies to prevent and treat visual loss. Two less common causes of untreatable optic nerve blindness are Leber Hereditary Optic Neuropathy (LHON) and autosomal dominant optic atrophy (ADOA) which occur in younger age groups than most cases of glaucoma, and hence sufferers may experience substantial physical, emotional and economic hardship. Over a 10 year period we have seen large numbers of patients with all three eye conditions and have developed a powerful study to determine the genes which cause optic nerve blindness and their relative importance. The research is gathering momentum and the genetics of all 3 conditions are now partly understood. This project seeks to analyse a new major glaucoma gene (Optineurin) in our Australian population and to try to understand the way in which a number of genes interact to cause blindness in some patients but not others. This work will lead to greater understanding of these causes of blindness and is likely to lead to new screening tests to know who is at most risk, and the opportunity to develop and test new treatments targeted to the underlying genetic problem.Read moreRead less
INTRARETINAL OXYGEN CONSUMPTION AND THE PREVENTION OF HYPOXIA IN RETINAL ISCHEMIA
Funder
National Health and Medical Research Council
Funding Amount
$164,444.00
Summary
Adequate oxygen supply to the retina is critical for normal visual function. The oxygen is normally supplied by the blood flowing in the two circulations that support the retina. These are the choroidal circulation, lying behind the retina, and the retinal circulation, which supports the front half of the retina. The retinal circulation is particularly vulnerable to vascular disease and insufficient blood flow (ischemia). Vascular changes are involved in a wide range of retinal diseases which ar ....Adequate oxygen supply to the retina is critical for normal visual function. The oxygen is normally supplied by the blood flowing in the two circulations that support the retina. These are the choroidal circulation, lying behind the retina, and the retinal circulation, which supports the front half of the retina. The retinal circulation is particularly vulnerable to vascular disease and insufficient blood flow (ischemia). Vascular changes are involved in a wide range of retinal diseases which are currently responsible for the majority of new blindness in our community. The choroidal circulation is relatively robust, and offers a potential avenue for increasing oxygen delivery to the retina in the clinical management of ischemic retinal diseases. The feasibility of such an approach is strongly dependent on the oxygen requirements of the retina, and how this is influenced by retinal ischemia. We plan to find out how much oxygen is consumed by the many different layers within the retina under normal conditions and then determine how this changes under ischemic conditions. We will then see if we can supply enough oxygen from the choroid by a combination of raising the oxygen content of the blood, increasing choroidal blood flow, and reducing the amount of oxygen used by the outer half of the retina. Our experiments will be done in laboratory rats, but the same principles are readily transferable to humans if they prove to be beneficial in protecting the retina from ischemic damage. Our study will also quantify the relationship between oxygen levels in the blood stream, and those in the different layers of the retina. This information may prove valuable in the treatment and the prevention of other retinal diseases where the manipulation of the intraretinal oxygen environment is an exciting new avenue of research.Read moreRead less
Pterygia, one of the most common ocular complaints in Australia and worldwide, are thought to originate from overexposure to UV light. We propose that UV-irradiation stimulate certain cells in the eye to produce cytokines, growth factors and enzymes which degrade scaffold proteins such as collagens. These enzymes may play a key role in the progressive and invasive nature of pterygia. Dissecting the mechanism(s) by which UV light induces these proteins will lead to new and more reliable therapies ....Pterygia, one of the most common ocular complaints in Australia and worldwide, are thought to originate from overexposure to UV light. We propose that UV-irradiation stimulate certain cells in the eye to produce cytokines, growth factors and enzymes which degrade scaffold proteins such as collagens. These enzymes may play a key role in the progressive and invasive nature of pterygia. Dissecting the mechanism(s) by which UV light induces these proteins will lead to new and more reliable therapies for the treatment of pterygia.Read moreRead less