Investigating nucleic acid gene therapy in brain and muscle
A central question of this research is to understand the biological constraints under which safe and effective cellular and, more particularly, molecular repair of the adult central nervous system (CNS) might be achieved. The origins of this work can be traced to experiments in which cellular transplantation was investigated as a strategy for the repair of genetic disorders of the CNS. Subsequently this research broadened to investigate the potential of viral vectors for gene delivery and direct molecular repair. We have investigated the requirements for cell-specific gene delivery and the delivery of functional genes in the nervous system.A major area of work has been to understand the immunological properties of viral vectors. Not only do viral vectors elicit immune responses in the CNS, but the severity is enhanced where the immune system is primed to the viral antigens. This can lead to widespread CNS inflammation, the elimination of reporter transgene expression and evidence of demyelination. Current research is directed to understanding these phenomena further and to developing strategies to abrogate the immune response.
The other major avenue of current work is the investigation of catalytic RNA molecules (ribozymes) for gene therapy and molecular repair. We are attempting to combine ribozyme technology with viral delivery to achieve this in the CNS. The ability of hammerhead ribozymes to downregulate the expression of target genes in the nigrostriatal dopamine system is being studied, the degeneration of which is implicated in Parkinson's disease. We are also exploring the potential of these ribozymes for gene function studies in the CNS. Finally the potential of another ribozyme, the group I intron, is being investigated for direct RNA repair in the genetic disorders myotonic dystrophy and Huntington's disease.
COLLABORATORS
Dr Harry Charlton, Department of Human Anatomy and Genetics, Oxford
Professor Kay Davies, Department of Human Anatomy and Genetics, Oxford
Professor Angela Vincent and Dr David Beeson, Weatherall Institute of Medicine, Oxford
Professor Paul Harrison and Dr Phil Burnet, Department of Pscychiatry, Oxford
Professor Kaj Taira, University of Tokyo, Japan
Professor Young Kim, National Genome Information Centre, Korea
Dr David Morrissey, Sirna Therapeutics, Boulder, Colorado, USA
CURRENT FUNDING
We receive funding and support from a range of organizations including; the Wellcome Trust, the UK Department of Health, the Marie Curie Foundation, the Royal Society, the DANA Foundation, Sirna Therapeutics and Oxford Biomedica.
FURTHER INFORMATION
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