I14 Translational potential of cholesterol supplementation-based strategies for huntington’s disease

There are numerous studies showing a reduction in cholesterol biosynthesis in the brain of different HD animal models of HD since pre-symptomatic stages, with the striatum being more affected compared to other brain tissues (Valenza et al., 2005; 2007; 2010; Shankaran et al., 2017). Abnormalities in brain cholesterol homeostasis are also present in HD patients: the specific brain cholesterol metabolite 24-hydroxy-cholesterol (24OHC) is progressively reduced in the plasma of HD patients and in pre-HD manifesting individuals who are close to the onset of the disease (Leoni et al., 2008; 2013). On the other hand, we reported that supplementation of a low dose (˜20µg) of cholesterol to the brain, through polymeric nanoparticles (NPs) modified with a peptide to cross the BBB, ameliorates synaptic and cognitive defects in R6/2 mice (Valenza et al., 2015), providing the proof of concept that providing exogenous cholesterol to the brain is beneficial in HD. In a more recent study we used three escalating doses of cholesterol (20, 250 and 500µg) infused directly into the striatum of R6/2 mice through osmotic minipumps, to identify the optimal dose of cholesterol from a therapeutic point of view. After a 4-week-period of intrastriatal infusion, all three doses of cholesterol were able to protect R6/2 mice from cognitive decline. With respect to motor abilities, only the highest dose of cholesterol was found to significantly ameliorate motor abnormalities. This dose also rescued functional and ultrastructural synaptic defects, enhanced endogenous cholesterol biosynthesis and significantly reduced mutant Huntingtin aggregates in the striatum of HD mice. Based on these findings, a second generation of g7-NPs (Belletti et al., 2018), with a different formulation and an increased cholesterol loading capacity compared to the previous ones (Valenza et al., 2015), have been recently developed and will soon be tested in order to move forward towards the clinic.