I joined the Department in 1994 and became a Departmental Lecturer in 2007. I have been a member of Professor Matthew Wood’s group the focus of which is gene therapy for degenerative disorders of the nervous system. Previous work in this laboratory, with which I was involved, was concerned with the development of gene delivery vehicles for the brain, predominantly viral vectors. The work is of relevance to the development of novel therapies for a range of neurological diseases including Parkinson’s and Alzheimer’s disease.
A prime focus of the earlier work was the investigation of neuropathological damage, in particular the immune response, elicited by viral vectors following delivery to the brain. The newer viral vectors developed for gene delivery are much less toxic and are now widely used for intra cerebral delivery. However despite this, potential limitations remain and direct injection into the brain is not ideal for all gene therapeutics for the nervous system.
For many purposes delivery of therapeutics to the brain via the blood stream would be more appropriate. A major hurdle for such delivery however, is the blood brain barrier (BBB). The BBB separates the circulating blood from the brain thereby restricting passage of substances into the brain. It is both a physical and metabolic barrier and is achieved largely by tight junctions present between the endothelial cells of blood capillaries in the brain. This barrier presents the main obstacle to successful transfer of neurotherapeutics including nucleic acids into target cells in the brain. A better understating of the nature of the barrier is critical therefore to the development of successful delivery vehicles for the transfer of therapeutics across it.
Moreover, developments in the understanding of BBB integrity, has important implications for the study of neurological diseases in general. For instance, the BBB is considered to be involved in the pathological process of several neurological diseases, in particular the neurodegenerative diseases. The BBB has also been considered to play a pivotal role in cognitive dysfunction present in the muscle wasting disease, Duchenne Muscular Dystrophy (DMD). Insight into BBB pathology should therefore improve understanding of its contribution to neurodegeneration in several diseased conditions.
I am therefore interested in studying BBB integrity in health and disease and good animal models in which to do this are the mouse models of DMD. A study of BBB integrity in DMD animal models has the potential not only to elucidate the contribution of the BBB to cognitive dysfunction in DMD but also to advance the understanding of other neurodegenerative diseases and to increase knowledge about delivery of neurotherapeutics across the BBB.
Neuronal surface and glutamic acid decarboxylase autoantibodies in Nonparaneoplastic stiff person syndrome.
Chang T. et al, (2013), JAMA Neurol, 70, 1140 - 1149
Tsc1 (hamartin) confers neuroprotection against ischemia by inducing autophagy.
Papadakis M. et al, (2013), Nat Med, 19, 351 - 357
Immunization against GAD induces antibody binding to GAD-independent antigens and brainstem GABAergic neuronal loss.
Chang T. et al, (2013), PLoS One, 8
Targeted neuronal nitric oxide synthase transgene delivery into stellate neurons reverses impaired intracellular calcium transients in prehypertensive rats
Li D. et al, (2013), Hypertension, 61, 202 - 207
Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks.
McMenamin MM. and Wood MJA., (2010), Gene Ther, 17, 448 - 458