Development of stem cell therapy for the treatment of retinal degneration

Lead Research Organisation: University College London
Department Name: Institute of Ophthalmology

Abstract

Hereditary retinal disease and age related macular degeneration (AMD) are major causes of irreversible blindness in the UK and involve the loss of the light sensitive photoreceptor cells in the retina. The lack of effective treatments for these conditions means there is a requirement to develop new therapies. The replacement of lost photoreceptors by cell transplantation is one possible approach, but transplanted cells need to make functional connections with the host retina. We have recently discovered that transplantation of immature photoreceptor cells from the developing retina into mouse models of retinal degeneration results in the integration of new photoreceptors that form functional connections with other retinal cells and improve visual function in these blind mice. Having defined the type of cell that is effective for retinal repair we now need to increase the number of new cells that integrate into the retina and find ways of generating the optimal type of immature cell in the laboratory. The adult retina contains retinal stem cells with the capacity to give rise to new photoreceptors in a cell-culture dish and these are a potential source of cells for transplantation that would avoid problems of rejection of foreign tissue.

The aim of this proposal is to develop strategies to replace missing photoreceptors in mouse models of retinal disease by transplanting retinal stem cells following various manipulations in the laboratory to optimise their development. We will investigate whether appropriate cells for transplantation can be generated by the introduction of genes that alter the stem cells themselves, and whether the introduction of genes into the retina receiving the transplant promotes increased levels of cell integration and enhances the improvement in vision. By determining the conditions for effective treatment of animal models using stem cells derived from the adult eye, we aim to provide the basic framework for developing similar approaches to treat human disease.

Technical Summary

Retinal degenerations are the leading causes of untreatable blindness in the Western world. Retinal repair by photoreceptor transplantation is a highly promising therapeutic approach. This proposal outlines a research programme designed to overcome several challenges facing the development of retinal cell transplantation therapies and is based on our recent research. In an MRC-funded study published in the journal Nature, we discovered that transplantation of immature rod precursor cells at a specific stage of development results in their integration and differentiation into rod photoreceptors that form synaptic connections and improve visual function in mouse models of retinal degeneration. This proposal aims to build on the novel concept that the ontogenetic stage of the donor cell is important for the success of transplantation. The four research objectives are: (i) to maximise the number of integrating cells. Increasing the number of integrating cells is likely to enhance improvements to visual function. We aim to optimise protocols for rod and cone transplantation and test whether modulating the outer limiting membrane, or the growth factor distribution, in the host retina enhances integration; (ii) to develop protocols for cone transplantation. As AMD involves degeneration of the cone-rich macular and most visual loss in retinitis pigmentosa is due to cone loss, cone transplantation may be of greatest clinical value. We will define the optimal ontogenetic stage for cone transplantation, adopting a similar experimental strategy as used to define optimal rod donor cells, and test whether newly integrated cones are functional in mice with cone defects; (iii) to determine the potential clinical application for photoreceptor transplantation. Our transplant studies indicate that transplanted rods survive and may enhance cone survival in models of retinal degeneration. We will determine if rod transplantation enhances survival of functional cones and quantify the effect of rod and cone transplants in longitudinal studies using a range of visual assessments including pupillometry, ERG and behavioural tests. (iv) to generate photoreceptor precursors from in vitro cultures of retinal stem cells derived from the ciliary margin of the adult eye. CM-derived cells are a promising source of optimal stage donor cells for transplantation and they raise the possibility of autotransplantation if they could be derived from a patient?s own eye. We will use viral vectors to express or suppress expression of key transcription factors known to be important for rod or cone generation and test whether CM-derived photoreceptor precursors are effective donor cells for transplantation.

Publications

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Ali RR (2011) Regenerative medicine: DIY eye. in Nature

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Barber AC (2013) Repair of the degenerate retina by photoreceptor transplantation. in Proceedings of the National Academy of Sciences of the United States of America

 
Description 'Technology and Innovation Futures Project Workshop'. Commissioned by Government Office for Science
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description British Retinitis Pigmentosa Society Project Grant
Amount £190,000 (GBP)
Organisation British Retinitis Pigmentosa Society 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2010 
End 01/2013
 
Description Fight for Sight, Project Grant
Amount £140,000 (GBP)
Organisation Fight for Sight 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 01/2010
 
Description MRC Programme Grant
Amount £2,300,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2012 
End 12/2017
 
Description MRC Project Grant
Amount £450,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2013
 
Description Riken Institute, Kobe, Japan 
Organisation RIKEN
Country Japan 
Sector Public 
PI Contribution We trained Japanese group in cell transplantation to retina
Collaborator Contribution Partly funded a collaborative exchange that enabled us to learn latest stem cell differentiation protocols from leading group.
Impact Resulted in an award being made by the Royal Society in recognition of the collaboration and to support a 3 month visit by one of the post doctoral researchers working on the project
Start Year 2008
 
Description BRPS AGM 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact British Retinitis Pigmentosa Society AGM

circulated research findings to patients
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description Departmental website 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Regular updates to departmental website giving an over view of work being conducted.

Attracted research funds from a donor
Year(s) Of Engagement Activity 2008,2009,2010,2011,2012
 
Description FBI AGM 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact AGM Fighting Blindness, Ireland

research circulated to patients
Year(s) Of Engagement Activity 2009,2010,2011,2012
 
Description Radio interviews 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviews on Radio 4 Today programme, BBC World Service and local radio stations about stem cell therapy for retinal degneration

Interest from public in our research - more email inquiries
Year(s) Of Engagement Activity 2010,2011,2012