Targeting activin receptors as a novel approach to promote myelin repair in the central nervous system

Oligodendrocytes are cells in the central nervous system that make myelin, an insulating layer around nerves that allows their normal functioning. Damage to myelin occurs in multiple sclerosis, contributing to lifelong problems with movement and sensation. Myelin repair can occur following this damage, and involves stem cells in the brain that multiply, survive and become new oligodendrocytes. However, as multiple sclerosis progresses, repair is less efficient and nerves don't function properly. Understanding what makes the stem cells multiply, survive, and become new oligodendrocytes is important in discovering new therapies that encourage myelin repair in MS. My studies show that a factor called activin-A is present in the brain during myelin repair, the stem cells in the injured brain have the receptors to respond to activin-A, and activation of these receptors can make these stem cells multiply, survive and become new oligodendrocytes in a dish. I predict that activin receptor activation in stem cells in the central nervous system drive myelin production and repair, and that activin receptors represent promising potential targets for a regenerative therapy for multiple sclerosis.

The overall aim of my proposal is to understand how activin receptors control stem cell behaviour during myelin production and repair.

The first objective is to identify when activin receptors could be activated on stem cells when myelin is being made or repaired, by looking at expression of activin receptors in the central nervous system of animal models.

As there are multiple forms of activin receptors, the second aim is to determine which one of these can stimulate stem cells, by seeing if stem cells can still respond to activin-A when specific forms of activin receptors are no longer expressed. Loss of expression of specific activin receptors will be done using cutting edge modification of the stem cell DNA. These stem cells will then be analysed for ability to multiply, survive and become new oligodendrocytes, and signal activation patterns inside the cell.

The third aim is to find out if other molecules that are known to activate activin receptors other than activin-A can also make stem cells multiply, survive, become oligodendrocytes and make myelin. Their expression in animal models when myelin is being made or repaired will be tested, and their effects on stem cell multiplication, survival and ability to become oligodendrocytes will be investigated.

The fourth aim is to find out whether activin receptor activation on stem cells is needed for myelin to be made or repaired, using an animal model where the receptors aren't present on the stem cells and seeing whether myelin is still made or repaired. We will also test whether stimulating activin receptors, using activin-A or the other molecules identified above, is able to drive myelin repair in an animal model where it normally doesn't happen, to model the failed myelin repair in multiple sclerosis.

The funding from this award would allow me to expand my research group, set up my independence and ask these important questions, which I believe could lead to the discovery of new strategies to encourage repair in multiple sclerosis. I believe that this research will show us the importance of activin receptors for stem cells in driving myelin repair, so that we can build on these findings to develop therapies for multiple sclerosis that stimulate these receptors.

I propose to test the contribution of activin receptor signalling to oligodendrocyte progenitor (OPC) responses during myelin production/repair in the central nervous system. Aim 1: to characterize activin receptor expression in vivo by immunofluorescence during developmental myelination and remyelination (both toxin- and immune-based lesion models). Aim 2: to determine the activin receptor subtype driving OPC responses relevant for myelination and remyelination, by CRISPR-mediated genomic deletion of specific receptor subtypes and analysis of OPC responses in vitro and following transplant into myelinating and remyelinating ex vivo brain explants, and receptor-specific pathway activation assessed by phospho-antibody microarrays. Aim3: to test effects of additional ligands either known to, or predicted to, bind activin receptors on OPCs, first by assessing expression during myelination/remyelination in vivo and then screening detected ligands for their potential to stimulate OPC responses using high throughput image acquisition and signalling pathway activation as above. Aim 4: to elucidate contribution of activin receptor signalling in OPCs to myelination and remyelination, by generating a constitutive and inducible OPC-specific conditional knockout for the activin receptor required for all activin receptor signalling, respectively, and crossing to reporter mice for analysis of knockout OPCs. OPC responses and myelination will be analyzed by immunofluorescence and ultrastructural analysis. Sufficiency of activin receptor stimulation in driving remyelination will also be tested by activin receptor ligand supplementation to demyelinated brain explants (to delineate effective concentrations) and in vivo to focal lesions of the central nervous system.
I envisage that this research will impact therapeutic strategies to promote myelin repair in human myelin disorders such as multiple sclerosis to decrease clinical impairments, by targeting activin receptors on OPCs.

My research would benefit beneficiaries such as researchers involved in the project, the pharmaceutical industry, patients with myelin disorders, and clinicians.

Researchers (short-term): The researchers employed and involved in this project (myself and postdoctoral fellow) would benefit directly from this research in that it employs cutting edge techniques such as genomic engineering, high throughput confocal imaging and antibody microarrays, that would significantly advance our scientific development. We would also be able to benefit from professional development opportunities provided by the university that would enhance our scientific performance and output.

Pharmaceutical Industry (short-term and long-term): My overall aim is to elucidate the role of activin receptor stimulation in oligodendrocyte progenitor cells in myelin production and repair, to identify potential therapeutic strategies to promote remyelination in multiple sclerosis. Activin receptor ligands could potentially be developed as therapeutics for this purpose in collaboration with a pharmaceutical company. Importantly, I am co-inventor on an intellectual property application for the use of activin-A and activin receptor stimulation to promote oligodendrocyte progenitor responses and myelin repair. This might lead to pharmaceutical companies buying out the patent in the near future, with positive economic consequences for the University of Edinburgh. I have had extensive collaborations/ consultancy with industry throughout my training, first with Novartis and now as a partnership with Biogen Idec to identify additional regenerative factors released by anti-inflammatory microglia/ macrophages.

Patients/ Public & Clinicians (long-term): This proposal has implications for development of therapeutic strategies to promote myelin repair in multiple sclerosis (in adults). In addition this can be extrapolated to treatment of myelin disorders in development, e.g. cerebral palsy. These diseases are characterized by failure of oligodendrocyte progenitor-driven myelin production. Thus, the identification of a potential therapeutic that could encourage this via stimulation of activin receptors on progenitor cells within lesions could lead to effective treatments for both of these diseases. Given that in the UK, multiple sclerosis and cerebral palsy each affect 100 000 people, one may expect a large number of patient beneficiaries from my research in the long-term. This would result in improved quality of life and national health. Furthermore, this could lead to economic growth for the UK, given the cost of life-time treatment of these patients for diseases with no currently identified cure. Consequently, long-term results of my research could greatly enhance therapeutic options available to clinicians to treat these diseases.