Affiliations: Centre for Brain Research, University of Auckland, Auckland, New Zealand | Molecular Biology and Reproductive Technology Laboratories, South Australian Research and Development, Adelaide, SA, Australia | Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School, Boston | Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA | Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK | IRBM Promidis, Pomezia, Italy
Note:  Correspondence to: Russell Snell, Centre for Brain Research, School of Biological Sciences, University of Auckland, Private Bag 92019, Auckland 1010, New Zealand. Tel.: +64 9 3737599/Ext. 85059; Fax: +64 9 3737415; E-mail: [email protected]
Abstract: Background: Huntington's disease is a neurodegenerative disorder, typically with clinical manifestations in adult years, caused by an expanded polyglutamine-coding repeat in HTT. There are no treatments that delay or prevent the onset or progression of this devastating disease. Objective and Methods: In order to study its pre-symptomatic molecular progression and provide a large mammalian model for determining natural history of the disease and for therapeutic testing, we generated and previously reported on lines of transgenic sheep carrying a full length human HTT cDNA transgene, with expression driven by a minimal HTT promoter. We report here further characterization of our preferred line, OVT73. Results: This line reliably expresses the expanded human huntingtin protein at modest, but readily detectable levels throughout the brain, including the striatum and cortex. Transmission of the 73 unit glutamine coding repeat was relatively stable over three generations. At the first time-point of a longitudinal study, animals sacrificed at 6 months (7 transgenic, 7 control) showed reduced striatum GABAA α1 receptor, and globus pallidus leu-enkephalin immunoreactivity. Two of three 18 month old animals sacrificed revealed cortical neuropil aggregates. Furthermore, neuronal intranuclear inclusions were identified in the piriform cortex of a single 36 month old animal in addition to cortical neuropil aggregates. Conclusions: Taken together, these data indicate that the OVT73 transgenic sheep line will progressively reveal early HD pathology and allow therapeutic testing over a period of time relevant to human patients.