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.
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.
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.
Organisations
- Queen's University of Belfast, United Kingdom (Lead Research Organisation)
- Indiana University, United States (Collaboration)
- Remedi (Collaboration)
- Mayo Clinic (Collaboration)
- University of California, San Diego, United States (Collaboration)
- University of Cambridge, United Kingdom (Collaboration)
- Singapore Eye Research Institute (Collaboration)
Publications

Cahoon JM
(2015)
Intravitreal AAV2.COMP-Ang1 Prevents Neurovascular Degeneration in a Murine Model of Diabetic Retinopathy.
in Diabetes

Chambers SE
(2013)
The role of immune-related myeloid cells in angiogenesis.
in Immunobiology

Chambers SEJ
(2018)
The Vasoreparative Function of Myeloid Angiogenic Cells Is Impaired in Diabetes Through the Induction of IL1ß.
in Stem cells (Dayton, Ohio)

Chen M
(2014)
RAGE regulates immune cell infiltration and angiogenesis in choroidal neovascularization.
in PloS one

Chen T
(2015)
MicroRNA-199b Modulates Vascular Cell Fate During iPS Cell Differentiation by Targeting the Notch Ligand Jagged1 and Enhancing VEGF Signaling.
in Stem cells (Dayton, Ohio)

Cochrane A
(2017)
Quaking Is a Key Regulator of Endothelial Cell Differentiation, Neovascularization, and Angiogenesis.
in Stem cells (Dayton, Ohio)

Davidson CT
(2017)
Inhibition or deletion of 11ß-HSD1 does not increase angiogenesis in ischemic retinopathy.
in Diabetes & metabolism

Duh EJ
(2017)
Diabetic retinopathy: current understanding, mechanisms, and treatment strategies.
in JCI insight

Hookham MB
(2016)
Hypoxia-induced responses by endothelial colony-forming cells are modulated by placental growth factor.
in Stem cell research & therapy
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 |