Development of retinal transplantation as an animal model to test stem cell therapies for myelin diseases

Lead Research Organisation: University of Edinburgh
Department Name: Centre for Cardiovascular Science

Abstract

Stem cells can be used by scientists to form many of the different cell types that make up the human body. They offer exciting new possibilities for treating diseases of the human brain such as multiple sclerosis. By using human stem cells to grow new nerve cells in a dish, and then transplanting them into the brains of patients, we hope to repair the damage caused by the disease. The difficulty is that we have to be completely sure that these cells will not behave in a way that might make the brain damage worse, for example by growing uncontrollably and forming a tumour. Scientists believe that cells that have been completely turned into nerve cells will not cause these problems and will be effective at damage repair, but they do need to prove this each time they want to use a set of cells for treating groups of patients. At the moment this would be done by transplanting the cells into the brains of rats or mice. However, as the brain is a very complicated structure, it is extremely difficult to be completely certain that all the cells are behaving normally. This project proposes a new way of testing cells by placing them in the back of the eye of rats. The nerve fibres at the back of the eye are very similar to those damaged in diseases such as multiple sclerosis. Here, unlike the brain, the transplanted cells can be easily seen and tested. If successful, the project will both reduce the number of animals needed for testing stem cell treatments and also speed up the use of these treatments for brain diseases for which there is presently no cure

Technical Summary

Cell transplantation represents an important application for stem cell medicine, with potential therapeutic benefit deriving from a combination of cell replacement and stimulation of endogenous repair. Diseases of the central nervous system, with their enormous societal and social costs, represent important targets for such therapies. Of these, the diseases of myelin provide appropriate initial targets; the oligodendrocytes lost or damaged in these diseases represent a functionally homogeneous population which extensive animal studies have established can be replaced by transplanted cells and whose replacement does not require complex targeting strategies. Key problems with transplantation of human ES or iPS cell-derived oligodendrocytes are, however, comparison of efficacy and confirmation of safety. Transplantation into animal models is clearly required, but assessment of behaviour within the complex 3-dimentional environment of the brain is a significant problem and represents a major roadblock in the path to clinical delivery of stem cell medicines. Here, therefore, we will take advantage of the unique architecture of the retina to develop a new preclinical animal model that overcomes these problems. The axons of retinal ganglion cells run in a flat sheet over the surface of the retina prior to their exit into the optic nerve. In the nerve, these axons are fully myelinated but they remain unmyelinated in their retinal portion. This reflects a lack of cells with myelinating capacity rather than any intrinsic properties of the axons, as we and others have shown that transplantation of precursor cells for oligodendrocytes into this retinal nerve fibre layer results in myelination. As the retina can easily be accessed and visualised through the eye in living animals, and then removed and flat mounted for histological analysis that enables quantification of myelination simply by measuring the area of myelinated axons, this has the potential to provide a simple and accurate model of efficacy and safety of myelinogenic cell populations prior to clinical use.
 
Description BIRAX
Geographic Reach Europe 
Policy Influence Type Membership of a guideline committee
 
Description Bristol review
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
 
Description CFFC - gave presentation at workshop on Regenerative Medicine at the House of Lords, 23rd Oct, Charles ffrench-Constant
Geographic Reach National 
Policy Influence Type Participation in advisory committee
 
Description European Leucodystrophy association committee on imaging in leucodystrpohy. Prof Charles ffrench-Constant has a leading role in this committee meeting, Oct 2013.
Geographic Reach Europe 
Policy Influence Type Membership of a guidance committee
 
Description Panel discussion at the House of Lords. Tuesday 30 October 2012, London. Charles ffrench-Constant was aksed to give evidence to the Science and Technology Select Committee at the House of Lords. They recently launched their regenerative medicine inquiry and Charles was asked to give oral evidence by being a member of panel (session lasted 55min). In accordance with Lords usual practice, possible questions were provided in advance and the session were be in public and transcribed. The House of Lords Science and Technology Committee, under the Chairmanship of Lord Krebs, is conducting an inquiry into regenerative medicine. The Committee will be looking, in particular, at whether the UK is in a position to facilitate the translation of knowledge from world-leading research to treatments and to benefit from thecommercial opportunities that they present. It also seeks to explore how realistic some of the reported claims of regenerative treatments and therapies are, both in the UK andinternationally.
Geographic Reach Multiple continents/international 
Policy Influence Type Gave evidence to a government review
 
Description Fellowship scheme
Amount £100,000 (GBP)
Organisation European Leukodystrophy Association (ELA) 
Sector Charity/Non Profit
Country European Union (EU)
Start 03/2011 
End 04/2014
 
Description University of Edinburgh - MS Society Clinical Science Centre
Amount £35,000 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2011 
End 08/2014
 
Description Wellcome Trust Investigator award
Amount £1,900,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2015 
End 02/2020
 
Title ES differentiation into oligodendrocytes 
Description Protocol for differentiating ES cells into oligodendrocytes suitable for myelinating cultures and transplantation 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact Successful fellowship application to ELA 
 
Title retinal transplant model 
Description Retinal transplant assay to measure the proliferative potential of myelinating cell populations 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact validation of model for the field 
 
Description Braod image analysis 
Organisation Broad Institute
Country United States 
Sector Charity/Non Profit 
PI Contribution Definition of the problem of quantifying myelin sheaths
Collaborator Contribution Development of machine learning image analysi protocols
Impact none to date
Start Year 2017
 
Description Disc1 SC 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution New research tools - fibres
Collaborator Contribution Human cells and initial results
Impact none to date
Start Year 2017
 
Description ES cell collaboration 
Organisation University College London
Department MRC Laboratory for Molecular Cell Biology (LMCB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Stem cell culture prior to testing in vivo
Collaborator Contribution Expertise in ES cell biology provided to usProvision of cells with mutations causing neurofibromatosis, and expertise in the animal models of the disease
Impact Cell lines established in Edinburgh for testing in the retinal model as outlined in the original application
Start Year 2009
 
Description ES cell collaboration 
Organisation University of Edinburgh
Department Institute of Stem Cell Research Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Stem cell culture prior to testing in vivo
Collaborator Contribution Expertise in ES cell biology provided to usProvision of cells with mutations causing neurofibromatosis, and expertise in the animal models of the disease
Impact Cell lines established in Edinburgh for testing in the retinal model as outlined in the original application
Start Year 2009
 
Description Septin Werner 
Organisation Max Planck Society
Department Max Planck Institute for Experimental Medicine
Country Germany 
Sector Public 
PI Contribution Discovery of myelin abnormalities that might be explained by septin mislocalization
Collaborator Contribution expert advice and septin antibodies
Impact none to date
Start Year 2017
 
Description analysis of DISC1 function in neurogenesis 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Post doc in lab working with DISC1 mutant mice
Collaborator Contribution Specialist knowledge
Impact No outputs in 2012
Start Year 2009
 
Description work on CNS adult neurogenesis 
Organisation Hebrew University of Jerusalem
Country Israel 
Sector Academic/University 
PI Contribution Work not yet started
Collaborator Contribution Work not yet started
Impact No outputs in 2012
Start Year 2012
 
Description yale 
Organisation Yale University
Department School of Medicine
Country United States 
Sector Academic/University 
PI Contribution Expertise in stem cell biology and extracellular matrix
Collaborator Contribution expertise in vascular biology and stroke models
Impact Grant from NIH
Start Year 2014
 
Description Charles frrench-Constant lecture at MS Space North annual meeting 2013 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact MS Space North annual meeting, 16 August 2013, Exhibition Centre, Aberdeen, Scotland. Prof Charles ffrench-Constant was invited to give a keynote lecture. 150 patients with MS and their families attended. Lecture was recorded and is available online (214 views so far): http://www.mssociety.org.uk/ms-events/2013/06/ms-space-north-2013-aberdeen.

Part of a general objective of disseminating information concerning regenerative medicine, generating interest in this field.
Year(s) Of Engagement Activity 2013
URL http://www.mssociety.org.uk/ms-events/2013/06/ms-space-north-2013-aberdeen
 
Description Edinburgh science festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Questions afterwards

none
Year(s) Of Engagement Activity 2014
 
Description Presentation by Charles ffrench-Constant at MS Society Scotland Perth 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact 200 patients and staff attended the annual meeting of the Scottish MS Society, where I explained the issues surrounding stem cell transplantation that are addressed by this grant

Further requests to talk to MS groups eg Ayr and Arran and Perth and Kinross, both in 2010
Year(s) Of Engagement Activity 2010
 
Description RSE lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Health professionals
Results and Impact Discussion about MS therapies

None
Year(s) Of Engagement Activity 2014
 
Description Talks to MS Society meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact Platform presentations at MS Meetings for patients

Dissemination of information, and funding donations to Society
Year(s) Of Engagement Activity 2008,2009