CELL THERAPY FOR THE VASODEGENERATIVE STAGES OF DIABETIC RETINOPATHY

Diabetic Retinopathy is a leading cause of visual impairment. Even with current management regimens it continues to significantly reduce the quality of life for millions of affected individuals. Late stages of diabetic retinopathy can be treated or contained to some extent by pan-retinal laser photocoagulation but at the expense of causing damage to large areas of functional retina. Although a range of other therapeutic approaches are being developed, most are directed to end-stage retinopathy and fail to address the early pathology characterised by microvascular cell dysfunction and death. New treatments focusing on these early changes such as cell therapies to repair/replace abnormal diabetic vasculature are needed. This study will establish the baselines for the development of a novel ?stem cell? therapy based on induction of therapeutic angiogenesis by introducing highly defined populations of bone marrow-derived endothelial progenitor cells (EPCs) into the ischemic retina.

Although EPCs have been shown to promote effective revascularisation of ischemic hearts in animal models, their definitive role in the ischemic retina remains unclear. This study will thoroughly assess any benefit obtained from injecting distinct EPCs into the vitreous of ischemic retinas.
Recently, it has been suggested that EPCs from type 1 diabetic patients are dysfunctional and display a reduced capacity to promote vascular repair. We plan to fully evaluate the function of EPC populations isolated from diabetic mice, and will test, for the first time, the possibility of healing diabetic dysfunctional progenitors by treating them with a statin.

EPCs are a highly heterogeneous group of cells. Depending on the subpopulation that is injected into the ischemic retina we anticipate promoting vascular repair by transplanting progenitors that become endothelial cells. Other EPC subpopulation transplants could actually exacerbate retinal damage by becoming inflammatory cells and this response this is important to determine. This study will clearly define the cell type with the capacity to promote vascular recovery and, importantly, will evaluate retinal function after cell therapy.
It is expected that endothelial progenitors from diabetic mice will be dysfunctional. We anticipate obtaining these cells from marrow, expanding them in the laboratory, correcting any inherent defect using statin treatment prior to ?transplanting? them into donor eyes. We expect that this approach will address the progressive retinal vascular damage that happens in diabetes and, ultimately, prevent vision loss.

Diabetes mellitus is increasing at an alarming rate and it has been estimated that by the year 2010 the total number of people with diabetes will reach 221 million worldwide. There are many complications of diabetes, but retinopathy remains the most common. Linked to the persistent fluctuations in blood glucose, dyslipidaemia and/or hypertension experienced by patients with diabetes, retinopathy constitutes a leading cause of blindness and visual impairment in the UK and the western world.
Currently available treatments for diabetic retinopathy such as pan-retinal laser photocoagulation, vitreoretinal surgery, and recently introduced growth factor inhibitors are mainly focused on late, end-stages of the disease. Importantly, these therapies do not address the primary pathology of retinal neurovascular degeneration during diabetes that precedes pre-retinal neovascularisation and diabetic macular oedema. Fresh perspectives on the cellular and molecular mechanisms of diabetic retinopathy could lead to novel and much more effective prevention/reversal strategies. One such perspective is targeting the early and intermediate stages of vasodegeneration to enhance vessel repair and reverse ischaemia and prevent progression to the late, sight-threatening stages of diabetic retinopathy. For diabetic patients with an occluded retinal microvasculature, measures to preserve surviving vasculature and re-vascularise defunct capillary beds could extend the lifetime of the neuropile, reduce pathogenic output of vasoactive and neuropathic agents and ensure retention of serviceable vision.
The basis for the proposed novel therapeutic approach is to harness the vasoreparative potential of bone marrow-derived Endothelial Progenitors Cells (EPCs). These cells are recruited to sites of damage and promote vascular integrity in response to injury and/or reperfusion of ischaemic tissues. There is great discrepancy concerning the definition of EPCs but it is now widely accepted two distinct phenotypes exist. So-called, early EPCs (eEPCs) have low proliferative potential and monocytic features. They are recruited to sites of tissue damage where they promote vascular repair and angiogenesis in a paracrine manner by secreting many cytokines. There is little evidence for integration of eEPCs in pre-existing or neovasculature. The other cell-type, called Outgrowth Endothelial Cells (OECs), have high replicative potential and appear to incorporate directly into the vasculature, side by side with resident endothelial cells. Despite their potential, nothing is known about OECs interact with the specialised retinal microvasculature. It is important to establish the biological roles of OECs and eEPCs, determine how their response to the diabetic milieu and, importantly, their therapeutic utility for preventing or maybe even reversing diabetic retinopathy.