Development of a one and done epigenetic editing strategy for Huntington’s Disease.

Huntington’s Disease (HD) is a fatal disorder caused by mutations in the Huntingtin (HTT) gene. In healthy individuals, the sequence of the HTT gene contains 10 to 26 repetitions of the same three DNA letters, namely CAG. Conversely, in Huntington patients, these repetitions exceed the number of 27. This expansion determines the acquisition of toxic functions to the HTT protein, finally leading to the loss of neurons, a relevant cell type in the nervous system. In the last two decades, several approaches have been developed to treat HD, either by inhibiting the messenger that leads to the production of the mutated HTT protein or by inactivating the gene itself. Although promising data were obtained in pre-clinical studies, these strategies were either poorly effective. in patients or may fail to reach clinical testing due to potential risks associated to these treatments. In this project, we aim at developing a novel strategy to inactivate the mutated HTT gene, which promises to be more effective and safer than the previous ones. Particularly, we will use epigenome editing to alter the code that regulates activity of the mutated HTT gene, such that this gene would not be expressed anymore in the cells. We will conduct studies in relevant models of HD to prove efficacy and safety of this novel therapeutic strategy.