CELL THERAPY FOR THE VASODEGENERATIVE STAGES OF DIABETIC RETINOPATHY

Lead Research Organisation: Queen's University of Belfast
Department Name: Centre for Vision & Vascular Science

Abstract

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.

Technical Summary

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.

Publications

10 25 50
 
Description A Translational Vision Science Building
Amount £4,800,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2010 
End 07/2014
 
Description Analysis of the vasoreparative and anti-inflammatory potential of a myelomonocytic endothelial progenitor cell (EPC) sub-type for treating diabetic retinopathy
Amount £99,500 (GBP)
Funding ID 1891/92 
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2014
 
Description CAMKII: A Novel Therapeutic Target for Pathological Ocular Angiogenesis
Amount £162,196 (GBP)
Funding ID PG/11/99/29207 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2012 
End 06/2015
 
Description Cell therapy for ischaemic retinopathies
Amount £1,500,000 (GBP)
Funding ID 10JTA 
Organisation Sir Jules Thorn Charitable Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2011 
End 10/2016
 
Description Development of a novel approach for regenerating pericytes during diabetic retinopathy
Amount £169,196 (GBP)
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2012 
End 08/2015
 
Description Endothelial progenitor cell therapy for ischaemic retinopathy
Amount £159,000 (GBP)
Funding ID 1883/84 
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2014
 
Description Harnessing the tissue-protective potential of erythropoietin (EPO) to prevent diabetic retinopathy
Amount £88,000 (GBP)
Funding ID 10/0004138 
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description Repair of Diabetic Damage by Stromal Cell Administration
Amount £760,000 (GBP)
Funding ID 305736 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 12/2012 
End 11/2016
 
Description Circulating Angiogenic Cells 
Organisation Mayo Clinic
Country United States 
Sector Charity/Non Profit 
PI Contribution Shared working on CAC cells (sharing protocols, data, expertise)
Collaborator Contribution Providing cell isolation and characterisation skills
Impact US-Ireland NIH application (submitted 2014)
Start Year 2013
 
Description REDDSTAR 
Organisation Remedi
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution EU-FP7 network involving multiple European partners
Collaborator Contribution We are partners in the REDDSTAR grant based on harnessing the reparative function of stromal stem cells in diabetic vascular complications
Impact No outputs so far
Start Year 2013
 
Description SERI (Singapore) collaboration 
Organisation Singapore Eye Research Institute
Country Singapore 
Sector Public 
PI Contribution We are working together on animal models of vein occlusion. We are providing expertise on the model and delivery of stem cells.
Collaborator Contribution They will provide use of primate models
Impact Nothing yet
Start Year 2012
 
Description Sharing of reagents/resources 
Organisation University of California, San Diego (UCSD)
Department Department of Pathology
Country United States 
Sector Academic/University 
PI Contribution The collaboration was based on chemical synthesis expertise from the Case Western Partner (Prof Vicent Monnier)
Collaborator Contribution Sharing of AGE moieties for our research
Impact FASEB J. 2010 Dec;24(12):4816-24.
Start Year 2009
 
Description Use of iPS cell technology to provide pericyte progenitors for diabetic retinopathy 
Organisation University of Cambridge
Department Department of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Sharing of knowledge and resources. Joint grant to a charity. Visits between groups
Collaborator Contribution Sharing of knowledge and resources
Impact None yet
Start Year 2011
 
Description iPS-derived EPCs 
Organisation Indiana University
Country United States 
Sector Academic/University 
PI Contribution Development of iPS-based technologies and use of iPS-derived ECFCs (EPC) to reverse ischaemia in retina
Collaborator Contribution Joint working, shared expertise, joint publication
Impact Prasain N, Lee MR, Vemula S, Meador JL, Yoshimoto M, Ferkowicz MJ, Fett A, Gupta M, Rapp BM, Saadatzadeh MR, Ginsberg M, Elemento O, Lee Y, Voytik-Harbin SL, Chung HM, Hong KS, Reid E, O'Neill CL, Medina RJ, Stitt AW, Murphy MP, Rafii S, Broxmeyer HE, Yoder MC. Nat Biotechnol. 2014 Nov;32(11):1151-7.
Start Year 2013
 
Description Article for lay magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact I wrote a "lay article" on diabetic retinopathy - new appraoches and upcoming therapies.

Several follow-up emails from interested readers
Year(s) Of Engagement Activity 2011
 
Description JDRF Charity information day, Belfast 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact The Juvenile Diabetes Research Foundation organised a patient and supporters information day and I was asked to present my research on diabetic retinopathy.
There was considerable interest and discussion after the formal presentation and for periods afterwards.

Several patients have visited our unit to meet the researchers.
Year(s) Of Engagement Activity 2011
 
Description Patient groups 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The talk was presented to patients and fund-raisers for ophthalmic research. They were given the opportunity learn about basic research ongoing in our laboraotry and the potential for transaltion into patient care.

Those attending were excited by the possibilities and interested to know how science is conducted
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014