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

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.

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.

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).