Targeting neurons with cholesterol. How can it change the future of Huntington Disease patients

Huntington Disease (HD) is a progressive, fatal, adult-onset and rare neurodegenerative disease. Currently, there is no effective therapy for this disease. In our studies, we found that in the brain of animals carrying the gene that causes HD there is a reduced capacity to produce cholesterol. This defect may have deleterious consequences, as brain cholesterol is important for neuronal function and it cannot be provided through the diet but is produced locally. Human subjects carrying the HD mutation may also exhibit a similar loss in brain cholesterol, as one of the brain cholesterol derivatives (24-hydroxy-cholesterol) that can be measured in blood is also found reduced. We therefore tried to counteract cholesterol reduction and its deleterious consequences by delivering new cholesterol to the brain of HD mouse models. In our first attempt we injected nanoparticles (NPs) loaded with cholesterol into the peritoneum of animals. The NPs (and the cholesterol attached to them) were able to enter the brain and to ameliorate some aspects of the disease. With this new proposal, in collaboration with G. Tosi (University of Modena), we will now test a new generation of NPs characterized by a higher cholesterol loading capacity. After evaluating their safety, and the level of exogenous cholesterol found in brain, we will perform functional and molecular studies to assess the therapeutic efficacy of this supplementation. This work will be conducted in two animal models of HD to further verify efficacy and relevance of cholesterol based treatments. Should results meet expectations, we will advance significantly towards the concept of brain cholesterol administration as a candidate therapeutic strategy in HD.