Full-length human mutant huntingtin with a stable polyglutamine repeat can elicit progressive and selective neuropathogenesis in BACHD mice.
humans The most important rationale for modelling human disorders in a non-human organism is the identification of fundamental pathogenic mechanisms that lead to novel therapeutic targets, and the evaluation of the efficacy and safety of potential new drugs. Historically, mice have been used to model human disease because of their physiological, anatomical and genomic similarities to humans. For neurodegenerative diseases, the mammalian neuronal physiology and the human-like brain anatomy makes mouse models especially useful. Nevertheless, their short life span of approximately 2 years is a serious limitation for late-onset neurodegenerative disease and the nervous system of humans is significantly more similar to that of primates. However, the costs and logistics of performing large-scale therapeutic trials in non-human primates are prohibitive. The question therefore remains about whether any positive outcome from therapeutic trials in mice is sufficient evidence to proceed with studies in humans. An alternative question is whether human trials should commence when a drug against a compelling target has been identified that did not show efficacy in mice. The reality: the predictive value of therapeutic trials in mice For amyotrophic lateral sclerosis (ALS), the most widely used mouse model has proven to be of poor predictive value: approximately 3% of all cases of ALS are caused by point mutations in the superoxide dismutase (SOD1) gene, and the most commonly used ALS mouse model expresses human mutant SOD1 (G93A) as a transgene (Gurney et al., 1994). A recent review summarized 78 individual and 12 combination compound trials that have been conducted using this mouse model (Benatar, 2007), which subsequently led to 11 double-blind, placebo-controlled clinical trials in humans, all of which failed (Vincent et al., 2008). Even compounds such as creatine, minocycline or cyclooxygenase-2 inhibitors that were most promising in mouse trials (Klivenyi et al., 1999; Drachman et al., 2002; Zhu et al., 2002) have not yet been shown to be beneficial in human clinical trials (Groeneveld et al., 2003; Shefner et al., 2004; Cudkowicz et al., 2006; Gordon et al., 2007). Riluzole remains the only FDA approved drug for ALS (Miller et al., 2003). The SOD1 mouse model more closely resembles familial than sporadic ALS and the possibility of biologically relevant differences between these forms of the disorder might limit the usefulness of the model. In addition, treatment in mice is commonly started before the onset of symptoms; this cannot be replicated in predominantly sporadic human diseases, such as ALS. These serious limitations apply to all diseases where familial and sporadic forms exist, such as Alzheimer’s and Parkinson’s diseases. Therapeutic trials for Huntington disease (HD), however, have significant advantages: the expansion of a polyglutamine tract in the huntingtin HTT protein has been determined as the single cause of the disease (The Huntington’s Disease Collaborative Research Group, 1993). Therefore, it should be easier to generate an accurate mouse model of HD than for other conditions with multiple, often unknown, causes. Furthermore, predictive testing is available to accurately predict whether, and when, a person will be affected (Tibben, 2007), making presymptomatic treatment in humans a feasible option. To assess the efficacy of potential therapeutics in the HD mouse model, multiple endpoints have been established that allow the monitoring of neuropathological and behavioural changes in the YAC128 HD mouse model (Table 1) (Slow et al., 2003; Van Raamsdonk et al., 2005a; Van Raamsdonk et al., 2005b).