Prof Steve Dunnett
Schematic illustration of the methods for preparation and implantation of embryonic cells as a dissociated cell suspension into the striatum of the adult rat brain. The embryonic mesencephalon contains the dopamine neurones lost from the host brain following 6-OHDA lesions of the dopamine fibre bundle in an experimental model of human parkinsonism.
Advances in our understanding of mechanisms of cell death, plasticity and regeneration in the central nervous system offer new opportunities for remediation and repair in several of the most distressing neurodegenerative diseases of adulthood, in particular Parkinson's and Huntington's disease. In the Brain Repair Group, we are seeking to develop new strategies for therapy based on a multidisciplinary approach in several converging problems:
- Models of disease
We require valid models of disease in order to evaluate novel treatments. We compare neurochemical, excitotoxic, metabolic and transgenic strategies, both in vitro and in vivo, for their accuracy in reproducing the specific patterns of neuropathology and mechanisms of cell death observed in human disease, and for their reliability in providing stable models within which to compare different treatments strategies.
- Neural transplantation
Improving the yield of surviving cells has turned out to be a key factor in viability of neural transplantation in Parkinson's disease, and this is likely to be of equal importance when applied to other neurodegenerative diseases such as Huntington's disease or multiple sclerosis. We are working to refine the methods for neural transplantation into the nervous system to yield optimal survival and growth of the implanted cells. Critical factors involve identification, dissection and handling of embryonic donor cells, and the surgical implantation protocols that maximise accuracy of placement and minimise trauma both to the host and to the implants.
- Alternative cells for therapy
The successful clinical trials of transplantation have to date all used embryonic donor tissues. However, whereas surgeries based on using human embryonic tissues can provide a 'proof of principle' the long term development and wider availability of neural transplantation is critically dependent on the identification of more readily available alternative sources of cells. We are actively exploring expanded populations of human stem cells, xenografts, and genetically manipulated cells and cell lines for their ability to provide safer and more readily available alternative to primary embryonic neurones for transplantation.
A complementary approach to cell transplantation (which involves replacing cells once already lost) is to protect damaged or traumatised neurones of the host brain from the assault of injury or disease. A wide number of compounds have been identified which have the potential to block processes of cell death and to promote regrowth of damaged cells, including growth factors, antiapoptotic agents, antioxidants and transcription factors. However a common problem for their use is that they don't get into the brain when injected or ingested peripherally. We are developing ways to deliver neuroprotective agents into precise sites in the brain both by engineering cells for transplantation ('ex vivo gene therapy') and by using viral vectors for direct intracerebral delivery ('in vivo gene therapy').
- Neurological assessment
The viability of each strategy needs to be evaluated in functional models of the disease. This requires development of behavioural and other functional models of assessment that are both sensitive to the neuroanatomical systems under investigation and relevant to the specific diseases targeted. A key component of our programme is to refine methods of functional analysis according to these dual goals, with a particular focus on objective operant tests of motor and cognitive function. We are also actively developing new strategies for imaging neurodegeneration and cell-based therapies in vivo, using the School's new 9.4T high field MR scanner.
EU FP7 collaborative research programme (E Cataneo, SB Dunnett and others) 2008. NeuroStemCell: Stem cell lines for cell-based therapies.
EU FP7 collaborative research programme (P Calabresi, SB Dunnett) 2008. REPLACES: Restorative plasticity and corticostriatal excitatory synapses.
Hereditary Disease Foundation (L Jones & SB Dunnett) 2007. Phenotypic characterisation of HD mice.
HighQ Foundation (AL Jones, SB Dunnett & SP Brooks) 2008. A comparative study of behavioural and molecular changes in mouse models of Huntington's disease.
MRC project grant (ND Allen, AE Rosser & SB Dunnett) 2008. Development of a platform to generate clinical grade neural progenitors for transplantation in Huntington’s disease.
Parkinson’s Disease Society (SB Dunnett, P Brundin, I Mendez & AE Rosser). 2007. Validation of a consensus protocol for preparing human embryonic nigral tissue in vitro and in vivo according to donor age, GMP preparation, and hibernation
Royal Society research grant (SB Dunnett) 2008. Additional coils to enable detection of 19F fluoro-dopa by MRI..
UKSCF/MRC Project grant (SB Dunnett & AE Rosser) 2008. Validity, specificity and yields of clinical grade primary and expanded human fetal cells for neural transplantation.
BBSRC equipment grant (AR Clarke, T Dale, SB Dunnett, A Harwood, D Riccardi & M Taylor) 2004. Confocal microscopy studies of neuroscience, signalling and development.
ESRC Project grant (P Atkinson, J Kitzinger, P Glasner, SB Dunnett & R Chadwick) 2006. RCSS696. Stem cells CBAR – CESAgen work package.
EU FP6 specific targeted research project (Z Kokaia, A Smith, M Hoehn, L Minicello, SB Dunnett & L Wikström) 2006. Towards a stem cell therapy for stroke.
Hereditary Disease Foundation (AL Jones & SB Dunnett) 2006. A comparison of behavioural and gene expression changes in rodent models of Huntington’s disease.
Hereditary Disease Foundation (MD Döbrössy & SB Dunnett) 2006. Characterizing BAC transgenic mice lines expressing GFP under the control of D2 and M4 promoters corresponding to the striatal indirect and direct pathways, respectively.
MRC 5 year project grant (SB Dunnett & AE Rosser) 2006. Development and validation of functional cell therapies for Huntington’s and Parkinson’s diseases.
Parkinson’s Disease Society research grant (SB Dunnett & C Monville) 2005. Understanding and eliminating the dyskinetic effects of nigral grafts.
Prof Anders Björklund & Dr Deriiz Kirik, University of Lund, Sweden.
Drs Marc Peschanski & Philippe Hantraye, INSERM/CNRS, Paris, France.
Prof Deniz Kokaia & O Lindvall, University of Lund, Sweden.
Prof Patrik Brundin, University of Lund, Sweden.
Profs I Mendez and H Robertson, Dalhousie University, Halifax, Nova Scotia.
Prof Elena Cataneo, University of Milan, Italy.
Prof Paulo Calabresi, University of Rome, Italy.
Prof Bernhard Landwehrmeyer, University of Ulm, Germany.
Prof Guido Nikkhah & M Döbrössy, University of Freiburg, Germany.
Dr Roger Barker, Prof John Pickard & Dr Jenny Morton, University of Cambridge.
Dr Lesley Jones & Dr Eddie Wang, School of Medicine, Cardiff University.
Drs Monte Gates & Rosemary Fricker Gates, Keele University