Issue 103, December 2008
The generation of a transgenic sheep model of Huntington's Disease:
This article is a summary of the speech given by Jessie Jacobsen at the Huntington's Disease Conference held in Christchurch 20/21 September 2008
progress to date and plans for the future
Despite the identification of the gene which causes Huntington's disease 15 years ago, the development of an effective treatment remains elusive. The generation of animal models of the disease has allowed us to investigate the underlying disease mechanisms as well as screen for potential therapies. There are currently several rodent models of Huntington's disease which have been the source of most of the knowledge of the disease process to date. The majority of these rodent models are acute, juvenile onset models. At The University of Auckland (in collaboration with the South Australian Research and Development Institute and Massachusetts General Hospital, Harvard Medical School) we have generated a transgenic sheep model of Huntington's disease.
The unique feature of our sheep model is that we have the ability to mimic the late onset of the disease (due to their extended life span) which could yield results with therapeutic relevance to human. Their comparable brain structure to human makes them an attractive species to investigate underlying disease mechanisms and also makes them a good surgical model for the delivery of gene therapy agents (such as RNAi).
We have generated six founding animals which all express the full length human huntingtin gene with 73 CAG repeats. All six animals show expression of the gene at varying levels and four of the animals have been bred, with one of the lines into the third generation of animals. Analysis of this line (which we have named Kiwi) is showing some promising results - changes in the brain that are reminiscent of the human disease. Further analysis of animals at 18 months of age is currently underway, as is the analysis of the remaining lines. Investigation into the specific effects of the HD gene on various cell types in the brain will be conducted early next year with collaborators at Massachusetts General Hospital, Harvard Medical School using the very latest molecular biological techniques. The identification of cellular changes will critically inform the development of early disease markers.
The characterisation of pathological and molecular changes in the brains of these animals will enable us to assess the efficacy of potential drugs in treating the disease. Ultimately, our aim is to have one of our six founder animal lines fully characterised and available to research groups around the world to use in an effort to fast track treatments and therapies into the clinic.
A precise sheep model of Huntington's disease could lead to improvements in therapeutic protocols prior to clinical trials thereby decreasing the risk of late, expensive failures in drug trials. It could also provide an alternative research resource for the investigation of underlying mechanisms in HD and triplet repeat disorders. It is our hope that this model will help fast track treatments for HD into the clinic and so provide a better future for families touched by this tragic disease.