A History of Research into Macular Degeneration
Age-related Macular Degeneration, or AMD, is the leading cause of visual impairment and blindness. With an ageing population, the number of people living with the disease at end of life will increase. The disease is associated with Loss of the retinal pigment epithelial cells at the back of the eye which support photoreceptor survival and function in the light detection.
The Clem Jones Centre for Regenerative Medicine was first established in 2011 through funding from the Clem Jones Foundation to support research into a therapy for macular degeneration. Clem Jones AO was the longest serving Lord Mayor of Brisbane and a successful business and philanthropist. Since his death, his Estate and Foundation have funded medical research, notably in the area of macular degeneration, since Clem Jones himself suffered the disease in his later years.
The Clem Jones Foundation continues to partially fund the work of the Centre, but the continuation of research is also dependent on government grant funding and donations from the public.
In dry AMD, or geographic atrophy, drusen deposits at the back of the eye lead to the death of the retinal pigment epithelial cells and subsequently photoreceptor dysfunction and death. Wet AMD or choroidal neovascularisation is associated with abnormal blood vessel growth and bleeding in the macula. Current treatments for wet AMD, including anti-VEGF injections, laser surgery and photodynamic therapy, help to control blood vessel growth and bleeding in the macula. However, there is no fully effective treatment available treatment for dry AMD.
AMD is now recognised as a disease highly amenable to stem cell therapy. Transplantation of retinal pigment epithelial cells is used to halt or reverse vision loss by preventing death of photoreceptors. It is considered one of the most viable applications of stem cells in the field of regenerative medicine.
An important long-term translational project has been the application of stem cell therapy to vision improvement in macular degeneration. Associate Professor Nigel Barnett discusses the Centre's research into age-related macular degeneration (AMD), the leading cause of blindness in the western world.
About the Clem Jones Centre for Regenerative Medicine
The Centre was established to investigate the therapeutic use of stem cells in tissue repair and disease. The goal is to combine research excellence in stem cell science with clinical translation, and to enhance, induce or transplant stem cells for patient benefit.
The Centre supports studies in the broader field of regenerative medicine and stem cell biology, combining stem cell science, biomaterials, tissue engineering, tissue regeneration, intelligent drug delivery, immunity and inflammation, and advanced surgery.
Research areas of interest include retinal diseases and degeneration, advanced therapies for vision loss, enhancement of hematopoiesis during ageing and disease, and regeneration of spleen from stem cells.
Research activities in the Centre
Advancing a stem cell therapy for macular degeneration
AMD is the most common cause of blindness in industrialised countries. Approximately 200 million people worldwide are impacted by the disease. Treatment options are limited and only partially effective.
Late-stage AMD is characterised by the dysfunction and death of retinal pigment epithelial (RPE) cells in the macula, and this is coupled with the breakdown of the underlying Bruch’s membrane. The RPE is a continuous sheet of brown nurse cells that maintains the function and health of the photoreceptors. Wet AMD is also characterised by neovascularisation, and the formation of new blood vessels at the back of the eye. In dry AMD, the combined loss of the Bruch’s membrane and RPE cells leads to photoreceptor dysfunction and death, which in turn causes visual impairment and blindness. While there are some treatment options for wet AMD, there are none for dry AMD.
A long-term goal in the Centre has been to develop a therapy for dry AMD by generating RPE cells from stem cells and safely transplanting them into the eye. The replacement of damaged RPE cells in AMD patients should halt or reverse vision loss by preventing the death of photoreceptor cells. Indeed, stem cell therapy remains the most promising therapy available for dry AMD for which there is currently no other treatment option.
The combined expertise of members of the whole Centre is focused on the development and testing of retinal implants as a potential treatment for blindness. Retinal implant constructs are comprised of sheets of stem cell-derived RPE cells supported by a prosthetic membrane, where the RPE cells grow and mature to form a uniform monolayer of pigmented cells which function like cells in the healthy eye.
In collaboration with surgical researchers at the University of Melbourne, the team has perfected procedures for implantation of prototype cell-on-membrane constructs into the rat eye. Fundus photography and Optical Coherence Tomography (diagram) depict the implanted construct in rat eye. Pilot studies have been promising, and provide a basis for further improvement and experimentation on constructs for cell delivery to human eyes.
Retinal diseases, degeneration and advanced therapies
Diseases under study include the common blinding conditions of age-related macular degeneration (AMD), diabetic retinopathy and glaucoma: diseases for which there are currently no cures. Using advanced experimental techniques, specialist imaging and electrophysiology, researchers in Nigel Barnett’s team work to unravel the complex steps which determine the death of the critical nerve cells in the retina. They are currently investigating a number of promising protective strategies to enhance the survival of retinal cells within the hostile environment of the diseased eye. Their goal is to develop effective therapies which can be used in the clinic to treat patients. These include the delivery of enhanced antioxidant compounds and the targeting of inflammatory responses within the retina.
In collaboration with Professor Steven Bottle (QUT), a rapid technique has been developed to quantify the efficacy of known and novel antioxidant compounds as novel therapies. This method uses a unique reversible fluorescent probe to assess cellular oxidative stress.
The team has developed pre-clinical animal models of retinal degeneration including AMD . These mimic the states of retinal oxidative stress and choroidal neovascularization. These models will be valuable in the testing of candidate drugs to slow down or even stop the degeneration of vital nerve cells and reduce the loss of vision currently associated with retinal disease.
The Centre has a history of work on the use of electrospun nanofibre membranes for the support of cell growth. Most work has been directed at the synthesis of a matrix for growing retinal cells with a view to making an implant for treatment of macular degeneration. A thin, porous biodegradable membrane is used to support monolayer growth of retinal pigment epithelial (RPE) cells. The thickness and fibre diameter of this synthetic membrane mirrors the physical properties of the native Bruch’s membrane at the back of the eye, and acts as a viable matrix for cells to attach and proliferate. Bond University holds a patent on the use of the membrane to support RPE cells as an implant to treat macular degeneration. Naomi Abbasi has joined the Centre to further develop a clinical-grade membrane modified in various ways to protect cells in the hostile environment of the diseased eye.
Retinal cells from stem cells
Cell therapy approaches to AMD treatment target the subretinal space between the photoreceptor layer and the damaged retinal pigment epithelium (RPE) so that transplanted cells directly interact with photoreceptors. An important consideration has been how to obtain enough of these rare cells to make an effective cell graft for transplantation. RPE cells derived from human pluripotent stem cells are now considered a suitable source of cells for cell replacement therapy. Stem cell-derived RPE cells have demonstrated significant safety and efficacy in several human trials.
The Centre is working to develop methodology for large-scale production of clinical grade retinal cells, suitable in terms of number and quality for transplantation into patients. Jason Limnios has a wealth of expertise in the growth and differentiation of human pluripotent stem cells. He has developed new methods for cell differentiation using small molecules to induce differentiation under completely feeder-free, xeno-free and chemically defined conditions. These approaches result in the rapid and efficient generation of retinal cells suitable for human clinical trials.
Hematopoiesis and lymphoid tissue regeneration
Hematopoiesis is the development of all blood cells, including cells of the immune system. Blood cell formation occurs primarily in bone marrow and involves hematopoietic stem cells. It is one of the most well-studied areas of stem cell biology. Transplantation of bone marrow or cord blood containing hematopoietic stem cells is currently the only FDA approved stem cell therapy. Techniques developed during the study of hematopoiesis are now being applied to the study of many different types of tissue-specific stem cells. The Centre has advanced their stem cell work to analysis at the single cell level, and is applying this technology to both hematopoietic and mesenchymal stem cells.
Centre staff are also investigating ‘extramedullary hematopoiesis’. This occurs primarily in spleen, a secondary lymphoid organ, in response physiological stressors like infection, pregnancy, blood loss and bone marrow failure. Spleen therefore has the ability to function as an important backup organ at times of stress and disease, providing extra immune cells to support an immune response. In line with this important function, spleen produces many myeloid cell types, which participate specifically in immunity to blood-borne pathogens and cancer cells. Importantly, spleen plays an essential role in controlling sepsis which follows infection with encapsulated bacteria.
Stem Cell microenvironments
The important role of cellular microenvironment in supporting stem cell differentiation in tissues is now well recognised. These ‘stromal’ cells provide signals and growth factors that support the maintenance, quiescence, differentiation and migration of stem cells. Helen O’Neill have been studying the contribution of mesenchymal and endothelial stromal cells to the formation of niches or microenvironments which support hematopoiesis in bone marrow and spleen. This work has been extended to grow new cellular microenvironments or ‘ectopic niches’ which support hematopoiesis in mice. This involves the transplantation of mesenchymal or endothelial cells under the kidney capsule in order to initiate a focus of hematopoietic cell development. These studies also investigate novel cell types and novel molecules as regulators of hematopoiesis.
Lymphoid tissue regeneration
Spleen has also been shown to have unusual regenerative capacity, and can regrow if fragments are transplanted on to other organs in the body. Jonathan Tan leads a team that has recently identified a stromal organiser cell essential for spleen tissue development. This cell type can co-ordinate the regeneration of spleen tissue and the formation of the immune cell compartments in new spleen tissue. The opportunity to harness spleen organogenesis for therapeutic benefit depends on identification of the structural stem cells necessary for spleen development and regeneration. Tan and his team have been studying the development and function of spleen grafts in a mouse model whereby cells are transplanted under the kidney capsule of mice to form mini-spleens.
- Professor Steven Bottle, Queensland University of Technology
- Professor Chen Chen, University of Queensland
- Dr Bob Bourke, Eye Specialist Institute, Gold Coast
- Dr Kiara Bruggeman, The Australian National University
- Professor Erica Fletcher, University of Melbourne
- Professor Mark Gillies, University of Sydney
- Dr Una Greferath, University of Melbourne
- Professor Damian Harkin, Queensland University Technology
- Associate Professor Ricardo Natoli, The Australian National University
- Professor David Nisbet, The Australian National University
- Professor Traian Chirila, Queensland Eye Institute
- Dr Brett Stringer, Flinders University
- A/Prof Michael Doran, Queensland University of Technology
- Professor Terry O’Neill, Bond University
- Dr Pravin Periasamy, National University of Singapore
- Dr Sawang Petvises, Thammassat University, Bangkok
- A/Prof Joseph Powell, Garvin Institute of Medical Research
- Professor Takeshi Watanabe, Kyoto University, Japan
- Dr Hong-Kiat Lim, Queensland Institute for Medical Research
NHMRC Ideas grant to Ricardo Natoli (ANU), Joshua Chu-Tan (ANU), Nigel Barnett (BondU), Ulrike Schumann (ANU), Stefanie Wohl (SUNY) - $1,189,692 (2021-2024) - Investigating microRNAs as key regulators in a novel communication pathway driving retinal degeneration
NHMRC Ideas grant to Nigel Barnett (BondU), Helen O'Neill (BondU) and Steven Bottle (QUT) - $683,000 (2020-2023) - Retinal stem cell therapy in the immunoprivileged eye
NHMRC - NSFC Joint Call for Research grant to Nigel Barnett and collaborators from University of Queensland, Queensland Eye Institute and Capital Medical University, China - $598,305 (2016 - 2020) - Biomarkers for the treatment and prognosis of sight-threatening diabetic retinopathy
NHMRC New Investigator Project grant to Jonathan Tan - $401,398 (2015-2018) - Understanding the mechanisms that regulate spleen organogenesis
ARC Discovery grant to Helen O’Neill - $390,000 (2013-2017) - Microenvironments which support extramedullary hematopoiesis
Philanthropic Donations: $261,000 (2016-2022) - Stem Cell Research
Donation from the Estate of Cora Cutmore to Bond University - Multiyear support - Stem Cell Research
Donation from the Clem Jones Foundation to Bond University - Multiyear support - Age-Related Macular Degeneration