ABSTRACT
Introduction ............................................................................................................ 166 Clinical Features of Huntington’s Disease ................................................... 166 HD Neuropathology ...................................................................................... 166 HD Molecular Genetics ................................................................................ 167 Advantages of Using Mouse Models to Study HD ....................................... 167
Mouse Genetic Models of HD for Preclinical Studies ........................................... 168 Validating Preclinical Mouse Models of HD ............................................... 168
Construct Validity ............................................................................. 171 Face Validity .................................................................................... 171 Predictive Validity ............................................................................. 172
N-Terminal Mutant Huntingtin Fragment Models........................................ 172 R6/2 Mice ......................................................................................... 172 N171-82Q Mice ................................................................................ 174
Full-Length Murine Huntington’s Disease Homolog KI Mouse Models ..... 175 HdhQ111 Mice ..................................................................................... 175 CAG140 Mice ................................................................................... 176 Hdh(CAG)150 Mice ................................................................................ 177
Full-Length Human Huntingtin Transgenic Mouse Models ......................... 178 YAC128 Mice ................................................................................... 178 BACHD Mice ................................................................................... 179
Summary of Preclinical HD Mouse Models ................................................. 181 Preclinical Trials with Mouse Models of HD ........................................................ 181
A Dual-Model Approach to Test HD Preclinical Candidates ....................... 182 Designing and Conducting Mouse Preclinical Trials ................................... 184
Power Analyses to Determine the Sample Size for the Study .......... 185 Rigorous Standardization of Preclinical Mouse Trials ..................... 186 Improving the Outcome Measures in Preclinical Mouse Studies ..... 186
Ever since its original description by George Huntington in 1872, Huntington’s disease (HD) has been known as one of the most devastating inherited neurodegenerative disorders af icting the human brain. Currently in the United States, there are about 30,000 patients with HD and another 150,000 people who are at a genetic risk of developing the disease. HD is characterized by the clinical triad of late-onset motor disturbances (i.e., chorea and dystonia), psychiatric de cits (i.e., depression, irritability, and psychosis), and cognitive decline (Bates et al., 2002). The majority of HD patients experience onset of symptoms around the age of 40 (adult-onset HD), and the disease relentlessly progresses until the patient’s death, which usually occurs within 10-20 years after disease onset. A small subset of HD patients experience the onset of symptoms before age 20 (juvenile HD), and these patients exhibit slightly different clinical features in that they tend to have more dystonia than chorea, as well as a higher incidence of epilepsy. Although the onset of HD is currently de ned by the onset of motor de cits, recent studies using more sensitive motor studies, as well as cognitive studies, indicate that clinical manifestations of HD may occur years to decades before the onset of motor symptoms, and such de cits may correspond to the early and progressive cortical and striatal atrophy seen in presymptomatic HD patients (Aylward et al., 2004; Rosas et al., 2005, 2006).
