I am currently working as a team member of Matthew Wood’s group on aspects of gene delivery to the CNS.  The work to date has been concerned with the development of gene delivery vectors for the brain, predominantly adenoviral vectors.  This work is of relevance to the development of novel therapies for a range of neurological disorders including Parkinson’s disease Huntington’s and Alzheimer’s disease.  Much of the recent work has centred on gene delivery to the dopamine neurons which degenerate in Parkinson’s disease. 

A prime focus of the earlier work has been investigating the neuropathological damage, in particular the immune response, elicited by viral vectors following their delivery to the brain.  The use of viruses, such as adenovirus, for gene delivery poses a particular problem where an individual may have been previously exposed to a similar virus.  Such an exposure could prime the immune system resulting in an exacerbated immune response when a similar vector is used for gene delivery.  This problem has particular relevance in the brain which was long thought to be somewhat immunoprivileged.  Our work has shown that, in spite of this, the brain is capable of initiating an immune response following delivery of high doses of adenoviral vectors and neuropathological damage has been demonstrated in the dopaminergic system, as a consequence of this.

The newer vectors, developed for gene delivery, are however, much less toxic enabling us to study other aspects of dopamine neuron degeneration.  Thus, we are exploring the use of lentiviral and adeno-associated viral (AAV) vectors to study the role of other molecules in dopamine neuron degeneration.  One such molecule is nitric oxide which is a potent cause of cellular oxidative stress, and accumulating evidence from human, animal and cellular studies implicate nitric oxide in the pathogenesis of dopamine neurodegeneration with implications for Parkinsons disease.  We are using lenti and AAV  vectors to deliver the nitric oxide synthase gene to dopamine neurons to investigate whether over-expression of nitric oxide can directly damage and cause degeneration of dopamine neurons.

Mary McMenamin