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Switching the disease off: Effects of spatial and temporal inactivation of mutant huntingtin in Huntington disease

Final Report Summary - SWITCH-HD (Switching the disease off: Effects of spatial and temporal inactivation of mutant huntingtin in Huntington disease)

Huntington Disease (HD) is a fatal, autosomal dominantly inherited neurodegenerative disorder, which is caused by an expanded CAG repeat in the huntingtin gene. In Europe, the annual cost per HD was estimated to be at least €30.000. Thus, despite the relatively small patient population there is an enormous socio-economic impact of HD. And the immense emotional burden placed on patients, their families, and their caregivers, represents a great challenge to society. A disease modifying treatment is urgently needed. Targeting specific mechanisms that are thought to be relevant to human disease pathogenesis is very challenging as there is only scant data from human studies to prioritize biological mechanisms. Given the monogenic nature of HD, targeted suppression of the mutant protein, mutant Huntingtin (mHTT), represents a promising strategy for therapy. While the most affected region in HD is the striatum, mHTT is expressed ubiquitously. Marked atrophy also occurs in other brain regions such as the cortex and the hypothalamus. The latter has been linked to disturbances in sleep pattern, energy metabolism and emotion, all of them non-motor symptoms of HD that often occur early in disease. Therefore, it is important to investigate which brain region to target to achieve amelioration of specific symptoms, and to determine when treatment should be started. For this purpose, preclinical studies using animal models are essential. EKUT has generated BACHD transgenic rats, which express full-length mutant human htt in the same developmental and tissue- and cell-specific manner seen in patients with the disease. These rats show motor deficits and neuropathological changes similarly as seen in HD patients. In this project, we further characterized these rats in terms of cognitive and psychiatric-like changes, evaluated potential biomarkers by neuroimaging and in peripheral tissue such as blood or CSF and investigated cellular mechanisms involving mHTT in primary neurons. The outcome of these studies served as read-outs to assess the efficacy of mHTT lowering in the striatum or the hypothalamus in BACHD rats. One major result of the study is that silencing of mHTT specifically in the lateral hypothalamus of BACHD rats with ssAAV1-miHTT rescued motor impairments regardless of the stage of disease, rectified food intake during growth phase, and reduced the amount of abdominal adipose deposits in the symptomatic stage when compared to the BACHD and wild-type littermates.