Transplantation of "super-OPCs" to improve central nervous system remyelination.

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Regenerative Medicine

Abstract

Multiple sclerosis (MS) is a common chronic disease of the brain and spinal cord, often starting in young adulthood, which frequently causes disability. Although the early stages of the disease can now be controlled with medication, in the later stages, when patients gradually develop more disability over time, there are no treatments to either slow, stop or reverse disability. One focus of research to help the later "progressive' phase of MS is to encourage repair of the myelin sheath that covers the nerves, similar to the insulation on electrical wires. This is damaged in MS and when replaced can protect nerves from dying, and avoid disability. The cells that carry out repair of this myelin sheath are called oligodendrocytes, which come from oligodendrocyte progenitor cells (OPCs), a form of stem cell. These cells are present in brains, but they struggle to repair the myelin sheaths in MS as they are cannot function well in the toxic environment in MS damaged areas.

In this project, we will test whether we can genetically change OPCs in a dish to make them unable to be harmed by a toxic MS environment. We will then transplant them into the brain and see whether this makes them more able to repair. We aim to do this by genetically modifying them to both help them to reach the areas of damage and then to make more myelin when they arrive. We will do this using human cells, testing them in a mouse model of MS, but if this is successful, we will then aim to do try this in a trial in humans.

This project will find out whether transplants of genetically modified OPCs into brains might in the future be turned into a helpful therapy for progressive MS.

Technical Summary

Multiple sclerosis (MS) is a common chronic inflammatory, demyelinating and neurodegenerative disease of the CNS which often starts in young adulthood, leads to disability, and as life expectancy is only slightly shortened, has major societal impact. There are now treatments that help reduce the relapses of early disease, but none which slow, stop or reverse disability progression in the later phase of MS. As disability reflects neurodegeneration, one focus of research into therapies to limit progressive disease involves enhancing repair of the demyelinated lesions (remyelination). This not only restores saltatory conduction but also metabolic support to the underlying axon. One such pro-remyelinating therapy is now in phase 2 clinical trial.
Remyelination is carried out by endogenous oligodendrocyte precursor cells(OPCs), which differentiate into mature myelinating oligodendrocytes. However, this fails in MS in part due to negative signals released from damaged tissue, preventing either OPC recruitment to areas of damage or blocking OPC differentiation. In this project, we will genetically modify exogenous human OPCs to not respond to negative migration cues. We will then transplant these into a mouse model of demyelination, and determine whether these are better recruited to areas of damage and improve remyelination, with or without a pro-maturation stimulus. As a proof of concept, we will use factors from our previous work which are involved in remyelination: we will abrogate the response to the chemorepellent Sema3A (expressed in MS lesions which fail to repair) by knocking out its receptor, and use 9-cis retinoic acid to activate the Retinoid X receptor as a pro-maturation factor.
These proof of concept experiments will be performed with human OPCs in a mouse in vivo model, to determine if this strategy may have future impact as a MS therapy. If successful, we aim to progress down the translational pipeline into first in man studies.

Planned Impact

Described in more detail in "Pathways to Impact" section.

Who will benefit from this research and how?

MS patients: patients are very enthusiastic about cell transplants, and this research will help determine if this is a feasible and effective potential future MS treatment, thus managing expectations. If the treatment works, the societal impact is large.

MS researchers: this project will answer the question as to whether exogenously transplanted OPCs are useful in improving CNS remyelination. We will share techniques of OPC in vitro assays, focal demyelination in slice culture assays, in vivo OPC transplants and generate a pool of manipulated human ESCs/NSCs/OPCs. This will be of interest to both public and private sector researchers.

Private sector companies e.g. pharma: there is much interest as to whether OPC transplants in MS are worth pursuing commercially. We have current shared projects with Genzyme-Sanofi and GSK, with discussions with other big pharma e.g. Merck-Serono, Biogen, and SMEs e.g. Aquila Biomedical.

Local, national and international policy-makers, for determining best use of funding: there is interest as to whether OPC transplants in MS are worth funding further for future therapies for MS (and similar diseases).

Publications

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Ferrari Bardile C (2019) Intrinsic mutant HTT-mediated defects in oligodendroglia cause myelination deficits and behavioral abnormalities in Huntington disease. in Proceedings of the National Academy of Sciences of the United States of America

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Milbreta U (2019) Scaffold-Mediated Sustained, Non-viral Delivery of miR-219/miR-338 Promotes CNS Remyelination. in Molecular therapy : the journal of the American Society of Gene Therapy

 
Description Do adult human oligodendrocytes remyelinate poorly and can we change this to better treat progressive multiple sclerosis?
Amount £600,000 (GBP)
Funding ID MRC/MS Society UK 
Organisation UK Regenerative Medicine Platform 
Sector Academic/University
Country United Kingdom
Start 12/2019 
End 12/2022
 
Description MS Centre
Amount £1,850,000 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2021 
End 12/2025
 
Description Roche
Amount CHF 900,000 (CHF)
Organisation F. Hoffmann-La Roche AG 
Sector Private
Country Global
Start 12/2017 
End 11/2019
 
Description Robin Franklin, University of Cambridge 
Organisation University of Cambridge
Department Cambridge Stem Cell Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution We have a post doc together. Most work will be done in Edinburgh.
Collaborator Contribution Training in spinal cord surgery to be done in Cambridge and use of a transgenic mouse in Cambridge.
Impact We will generate cell lines, but these are not yet finished.
Start Year 2017
 
Description Roche 
Organisation F. Hoffmann-La Roche AG
Country Global 
Sector Private 
PI Contribution Work on MS tissue
Collaborator Contribution Financial support for this work
Impact Paper in Nature 2019
Start Year 2018
 
Description SnRNAseq 
Organisation Karolinska Institute
Country Sweden 
Sector Academic/University 
PI Contribution Collaboration between us (MS neuropathology and biology experts) and Goncalo Castelo-Branco (experts in snRNAseq and analysis)
Collaborator Contribution Collaboration between us (MS neuropathology and biology experts) and Goncalo Castelo-Branco (experts in snRNAseq and analysis)
Impact Nature Medicine and Nature paper 2018 and 2019
Start Year 2017
 
Description BBC Alba programme on stem cells in MS 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview for BBC Alba TV show on stem cells in MS http://www.bbc.co.uk/programmes/b09jqvqv
Year(s) Of Engagement Activity 2017
URL http://www.bbc.co.uk/programmes/b09jqvqv
 
Description BBC Radio 4 broadcast 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact BBC radio 4 programme on MS with Caroline Wyatt
Year(s) Of Engagement Activity 2019
 
Description Careers in academia 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact post doc talking to schoolchildren about science careers
Year(s) Of Engagement Activity 2018
 
Description Follow-up interviews for YouTube for Shift-MS webpage 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Shift MS interview of me by MS patient, for webpage as a Youtube video
Year(s) Of Engagement Activity 2017
URL https://shift.ms/
 
Description Interview BBC scotland 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interview for MS Centre status re-awarded.
Interest from patients, general public
Year(s) Of Engagement Activity 2021
 
Description MS Society UK Ambassador 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Made ambassador. Spoke on panel at MS Society annual meeting and Women in science dinner
Year(s) Of Engagement Activity 2019
 
Description MS life Inverness - patient group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Patient group day for MS patients by MS society. About 50 people there. Much discussion.
Year(s) Of Engagement Activity 2017
 
Description Portraits of the brain 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact Art activities between patients and researchers to better understand MS over a period of 2 months
Year(s) Of Engagement Activity 2018
URL http://temp.crm.ed.ac.uk/seminars/portraits-brain
 
Description Press release on paper publication 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact press release for paper publication - interview for Glasgow herald newspaper, coverage in Scotsman paper and online science magazines
Year(s) Of Engagement Activity 2021
URL https://www.edinburghnews.scotsman.com/health/edinburgh-university-research-could-help-prevent-disab...
 
Description STOPMS panel 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Panel discussion for STOPMS campaign
Year(s) Of Engagement Activity 2020
 
Description Secondary Teachers talk, Roslin, Scotland 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Talk to secondary school teachers (biology) to update them on stem cells, especially in the context of MS.
Year(s) Of Engagement Activity 2017
 
Description interview with Understanding Animal Research 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact https://www.understandinganimalresearch.org.uk/news/a-new-animal-model-for-late-stage-multiple-sclerosis/
Year(s) Of Engagement Activity 2021
URL https://www.understandinganimalresearch.org.uk/news/a-new-animal-model-for-late-stage-multiple-scler...