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Aims  Huntington disease (HD) is a fatal neurodegenerative disorder with no disease‐modifying treatments approved so far. Ongoing clinical trials are attempting to reduce huntingtin (HTT) expression in the central nervous system (CNS) using different strategies. Yet, the distribution and timing of HTT‐lowering therapies required for a beneficial clinical effect is less clear. Here, we investigated whether HD‐related behaviours could be prevented by inactivating mutant HTT at different disease stages and to varying degrees in an experimental model.    Methods  We generated mutant BACHD mice with either a widespread or circuit‐specific inactivation of mutant HTT by using Cre recombinase (Cre) under the nestin promoter or the adenosine A 2A  receptor promoter respectively. We also simulated a clinical gene therapy scenario with allele‐specific HTT targeting by injections of recombinant adeno‐associated viral (rAAV) vectors expressing Cre into the striatum of adult BACHD mice. All mice were assessed using behavioural tests to investigate motor, metabolic and psychiatric outcome measures at 4–6 months of age.    Results  While motor deficits, body weight changes, anxiety and depressive‐like behaviours are present in BACHD mice, early widespread CNS inactivation during development significantly improves rotarod performance, body weight changes and depressive‐like behaviour. However, conditional circuit‐wide mutant HTT deletion from the indirect striatal pathway during development and focal striatal‐specific deletion in adulthood failed to rescue any of the HD‐related behaviours.    Conclusions  Our results indicate that widespread targeting and the timing of interventions aimed at reducing mutant HTT are important factors to consider when developing disease‐modifying therapies for HD.

Effects of mutant huntingtin inactivation on Huntington disease‐related behaviours in the BACHD mouse model