Investigating the neuroprotective and neuroregenerative properties of bone marrow stem cell mobilising drugs in Friedreich ataxia.

Friedreich Ataxia (FRDA) is a progressive neurological illness characterised by loss of mobility and co-ordination (ataxia). It is the commonest cause of inherited ataxia and symptoms usually become apparent in childhood. As well as causing problems in the nervous system, the disease may also lead to heart and metabolism problems. At the present time there are no treatments that can slow down, let alone cure, the condition, which usually leads to wheelchair dependency in early adulthood. Stem cell therapies are being developed for a variety of neurological and non-neurological conditions and preliminary evidence suggests that they may be of use in FRDA. Our initial studies have suggested that bone marrow-derived stem cells offer protection to nerve cells and cells derived from patients with FRDA. These stem cells are also able to improve some of the metabolic problems that FRDA causes. We hypothesise that mobilising stem cells present in the bone marrow of patients with FRDA may be a way of protecting cells within the body and thus reducing damage caused by the genetic disorder. There are a number of drugs that stimulate the release of stem cells from the bone marrow into the blood circulation. We believe that there are multiple ways in which such drugs could help, not just through mobilising bone marrow stem cells: they may have a direct protective effect on brain cells; they may promote nerve cell regeneration by stimulating stem cells known to reside in the brain; and they may also promote repair in non-neurological tissue, such as the heart. These experimental effects have been shown to be valuable in animal models of other degenerative neurological and cardiac disorders, where they clearly improve recovery. Such drugs are already in routine clinical use (mostly for diseases of the blood system, such as leukaemia), which has led to good evidence of their safety, so helping to accelerate future translational research into their use in other conditions. These drugs have also now begun to be tested in human clinical trials in patients with conditions ranging from motor neuron disease, stroke, Alzheimer's disease, and spinal cord injury to myocardial infarction.
Experimental studies undertaken within our laboratories clearly indicate bone marrow stem cells protect nerve cells and induce repair of the nervous system. We have demonstrated that human bone marrow stem cells help correct the effects of the genetic mutations in cells derived from patients with FRDA (increasing the expression of the protein, frataxin, which is reduced in FRDA); and increase their resistance to cell damage. We believe that studying stem cell mobilising drugs is the next rational step in defining mechanisms of nerve cell protection. We aim to further determine the mechanisms by which nerve cells may be protected or replaced by these drugs. We will test this in a variety of cell culture and animal models of FRDA. Translating the approach of using bone marrow stem cell mobilising drugs to clinical practice is very realistic, but depends vitally on experimental studies such as those we propose, exploring and understanding the therapeutic mechanisms of these drugs in order to allow the development of a potentially simple, non-invasive and effective neuroprotective and regenerative therapy in patients with FRDA.

Recent studies have suggested that bone marrow-derived stem cells offer protection to neurons via multiple and diverse actions. Furthermore, stem cell derived factors are able to improve some of the metabolic deficiencies seen in cell models of the progressive neurological condition Friedreich ataxia (FRDA), suggesting that transplantation or mobilisation of stem cells may be a potential therapy. Here we propose an exploration of the mechanisms by which bone marrow stem cell mobilising drugs may provide neuroprotection and influence regeneration in FRDA. We hypothesise that these drugs act via multiple mechanisms, with direct neuroprotective effects and secondary reparative effects through facilitation of neuronal regeneration by both intrinsic neural stem cells and mobilised bone marrow cells. We propose to use a combination of cell culture models and FRDA animal models. We will study direct neuroprotective effects of stem cell mobilising drugs on neuronal cultures and inducible pluripotent stem (iPS) cells derived from patients with FRDA. Differentiation of FRDA iPS cells into a neuronal phenotype will allow an analysis of the effect of these drugs on frataxin and mitochondrial signalling pathways. We will also use mouse models of FRDA and analyse the effects of administration of stem cell mobilising drugs. We will determine whether these drugs influence neuronal pathology and whether this is dependent on stem cell mobilisation. We will establish whether administration of these drugs increases entry of stem cells into the brain and whether these cells integrate with endogenous neurons. Using ex vivo cerebellar slices with electrophysiological and single cell PCR, we will determine whether integration of stem cells with endogenous cerebellar cells alters electrical properties or gene expression within the cerebellum. Understanding these therapeutic mechanisms will potentially allow the development of a novel neuroprotective therapy in patients with FRDA.

Beneficiaries:
Cell biologists in the field of neurological disorders, Cell biologists in the field of regenerative medicine, clinical neuroscientists, practising neurologists, commercial companies developing stem cell mobilizing drugs for future therapies or for means of mobilising specific bone marrow cell sub-populations, patients with degenerative disorders. Beneficiaries will be made aware of the research through publication in high quality journals, participating in international research conferences, interacting with research charities, public lectures and developing links with collaborators throughout the world.

In order to develop a 'medical stem cell mobilisation' therapy for Friedreich ataxia and related conditions, a deeper understanding of the basic science and biology of bone marrow stem cell mobilising drugs in the context of ataxic conditions is required. One substantial advantage of studying bone marrow stem cell mobilising drugs is the rapidity with which new observations can be translated into clinical studies. The medical use of these drugs to mobilise stem cells from marrow to circulation prior to peripheral blood stem cell harvest currently in other diseases has given us ample data concerning the safety of these drugs (e.g. granulocyte-colony stimulating factor (G-CSF)). These have been vital factors in the very rapid translation of experimental studies of bone marrow stem cells mobilising drugs in other disorders, including amyotrophic lateral sclerosis, stroke, Alzheimer's disease, spinal cord injury and myocardial infarction. In order to establish stem cell mobilising therapies for ataxic conditions detailed studies of the behaviour of in animal models of Friedreich ataxia are required. We anticipate a period of approximately three years of preliminary experiments before applying to conduct clinical trials.

Exploring and understanding the therapeutic mechanisms of stem cell mobilising drugs could allow the development of a conceptually simple, relatively cheap, non-invasive and effective neuroprotective and regenerative therapy in patients with degenerative disorders. We anticipate that our research will allow the development of stem cell mobilising agent trials in the future which have the potential to impact on long-term disability leading to an improved quality of life for patients. If trials prove successful, long term healthcare costs in treated individuals could be reduced and working lives/productivity extended.

This project will also support the academic training of talented researchers. It will also hopefully lead to start of high impact clinical trials, thereby helping to ensure quality in the future generation of scientists/clinicians participating in the emerging field of stem cell and regenerative medicine within the UK. This project will therefore assist in maintaining the UK as a world leader in regenerative medicine.

The University's Research and Enterprise Development (RED) unit will deal with any commercial exploitation of the research data obtained from this project.