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.
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.
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).
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
Dillenburg A
(2018)
Activin receptors regulate the oligodendrocyte lineage in health and disease.
in Acta neuropathologica
Meireles AM
(2018)
The Lysosomal Transcription Factor TFEB Represses Myelination Downstream of the Rag-Ragulator Complex.
in Developmental cell
Bergholt MS
(2018)
Correlated Heterospectral Lipidomics for Biomolecular Profiling of Remyelination in Multiple Sclerosis.
in ACS central science
Falcão AM
(2018)
Disease-specific oligodendrocyte lineage cells arise in multiple sclerosis.
in Nature medicine
Jäkel S
(2019)
Altered human oligodendrocyte heterogeneity in multiple sclerosis.
in Nature
Nicaise AM
(2019)
Cellular senescence in progenitor cells contributes to diminished remyelination potential in progressive multiple sclerosis.
in Proceedings of the National Academy of Sciences of the United States of America
Vanden-Hehir S
(2019)
Alkyne-Tagged PLGA Allows Direct Visualization of Nanoparticles In Vitro and Ex Vivo by Stimulated Raman Scattering Microscopy.
in Biomacromolecules
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
Matjusaitis M
(2019)
Reprogramming of Fibroblasts to Oligodendrocyte Progenitor-like Cells Using CRISPR/Cas9-Based Synthetic Transcription Factors.
in Stem cell reports
Lloyd AF
(2019)
Central nervous system regeneration is driven by microglia necroptosis and repopulation.
in Nature neuroscience
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
Bøstrand SMK
(2021)
Oligodendroglial Heterogeneity in Neuropsychiatric Disease.
in Life (Basel, Switzerland)
Zoupi L
(2021)
Selective vulnerability of inhibitory networks in multiple sclerosis.
in Acta neuropathologica
Neely S
(2022)
New oligodendrocytes exhibit more abundant and accurate myelin regeneration than those that survive demyelination
in Nature Neuroscience
Seeker LA
(2022)
Oligodendroglia heterogeneity in the human central nervous system.
in Acta neuropathologica
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 | How does oligodendrocyte transcriptional heterogeneity change biological function? |
Amount | £625,951 (GBP) |
Funding ID | BB/X002799/1 |
Organisation | United Kingdom Research and Innovation |
Sector | Public |
Country | United Kingdom |
Start | 06/2023 |
End | 06/2026 |
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 | SFr. 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... |