Huntington’s disease (HD) involves disruption in brain cholesterol homeostasis, with several HD animal models showing reduced brain cholesterol biosynthesis and levels. Providing exogenous cholesterol has been effective for improving phenotypes, but the existing methods used to deliver cholesterol are invasive and cannot be transferred easily to clinical practice.
In a study published in Translational Neurodegeneration, Monica Favagrossa, of Istituto Di Ricerche Farmacologiche Mario Negri IRCCS in Milan, Italy, and colleagues developed a method for nose-to-brain delivery of cholesterol. They used freeze-and-thaw methods to develop cholesterol-enriched liposomes, which were administered to R6/2 mice via the intranasal route once or repeatedly.
They used deuterated cholesterol to distinguish exogenous cholesterol from endogenous cholesterol. They measured exogenous cholesterol accumulation and distribution, along with the levels of cholesterol precursors and metabolites, by means of mass spectrometry. The researchers also conducted behavioral tests with the mice and performed real-time polymerase chain reaction analysis, immunostaining of mutant HTT aggregates to verify the therapeutic effects of liposomes, and a Simoa (single molecule array) assay to measure plasma neurofilament levels.
The results of the investigation demonstrated that exogenous cholesterol could spread throughout the entire brain after intranasal administration of cholesterol-enriched liposomes. Repeated treatments reversed cognitive decline and delayed the onset of impairment in coordination and motor skills, as well as loss of muscular strength, in early stages of the disease. In addition, cholesterol supplementation lowered plasma levels of neurofilament light chain and promoted clearance of mutant HTT aggregates.
Overall, these findings suggest that intranasal cholesterol supplementation could be an effective strategy in the treatment of HD, with potential for intranasal delivery. The authors note that this method has the advantages of being noninvasive and bypassing the blood-brain barrier, along with its potential for patient self-administration.
If implemented in clinical practice, this approach could improve treatment of HD while also providing a possible therapeutic approach for other neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, which also involve cholesterol deficits.