Cholesterol delivery using brain-permeable nanoparticles is a therapeutic option to reverse the behavioral decline related to Huntington disease (HD) and the neuropathologic signs of the disease in a mouse model, according to a new study published in the journal Pharmacological Research. These findings “highlight the therapeutic potential of cholesterol-based strategies in HD patients,” the authors wrote.
“The next logical step is to evaluate strategies for clinical implementation, bringing this promising therapy closer to real-world application,” wrote editorialists in an accompanying paper.
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Research has shown that in HD, cholesterol biosynthesis in the brain is impaired, and increasing its levels in a mouse model of the disease can have a positive therapeutic outcome, the investigators noted.
In the present study, a team of researchers tested the long-term efficacy of chronic cholesterol administration to the brain of a slow-progressing HD mouse model, which more closely resembles the disease in humans.
The team used second-generation cholesterol-laden brain-permeable nanoparticles, which gradually release cholesterol into the brain.
They used 3 treatment paradigms: “early,” “late,” and “early and late.” In the first, they treated the animals before they showed any signs of the disease; in the second, they treated them during the symptomatic phase; and in the third, they treated them twice, at both stages.
They found that 1-cycle treatment, “early” or “late,” was enough to normalize cognitive defects up to 5 months. It also improved other behavioral and neuropathologic parameters. The 2-cycle treatment led to therapeutic effects for more than 11 months and caused no severe adverse effects.
In terms of mechanism of action, the team showed that the motor and cognitive improvements following cholesterol treatment correlated with a reduction in mutant Huntingtin aggregates.
“Cholesterol delivery to the brain appears to be a safe therapeutic option for Huntington’s disease, capable of preventing or reversing cognitive and motor defects characteristic of the disease,” the editorialists concluded.
This article originally appeared on Rare Disease Advisor
- Birolini G, Valenza M, Ottonelli I, et al. Chronic cholesterol administration to the brain supports complete and long-lasting cognitive and motor amelioration in Huntington’s disease. Pharmacol Res. Published online June 17, 2023. doi:10.1016/j.phrs.2023.106823
- Martín MG, Dotti CG. Game-changer in the fight against Huntington’s disease: cholesterol nanoparticles restore brain function in mice. Pharmacol Res. Published online August 1, 2023. doi:10.1016/j.phrs.2023.106879