Exploring the therapeutic potential of cortical ADAM10 inhibition in Huntington’s Disease

Huntington's disease (HD) is a genetic brain disease characterized by the dysfunction of the cortico-striatal circuitry. Identifying drugs that restore its proper function is one of the main objectives of researchers working in the HD field. It is known that the selective expression of the mutant huntingtin protein in cortical neurons alters the functionality of the circuitry and the healthy status of striatal neurons. The cortical damage induced by mutant huntingtin protein is therefore sufficient to trigger HD pathology. This project focuses on ADAM10, an enzyme that is critical for the synapse. ADAM10 activity aberrantly increases in the Huntington brain. Our hypothesis is that the increased activity of the enzyme is particularly harmful in the cortex. In this study, we will develop a method to specifically inhibit ADAM10 in the cortex of a Huntington's disease mouse model and test its efficacy in preventing disease onset and progression. If this will be the case, therapies targeting the cortex and relying on ADAM10 inhibition could be developed. Furthermore, because the cortex is significantly more drug-accessible than the striatum, any positive finding will help us to speed up the development of ADAM10 inhibitors for clinical use.