Development of a novel intranasal oligonucleotide delivery approach for Huntington disease
Huntington disease (HD) is a progressive brain disorder affecting movement, mood, and cognitive skills, caused by inheriting a mutated copy of the huntingtin gene. This results in the production of a mutant huntingtin protein (mHTT) that is toxic to critical nerve cells in the brain. Reducing mHTT using specialized pieces of DNA, called antisense oligonucleotides (ASOs), should slow or prevent disease onset. However, ASOs cannot reach the brain when delivered into the bloodstream, due to the presence of the blood-brain barrier (BBB), and thus require surgical injection into the brain or the cerebrospinal fluid (CSF) that bathes the brain.
Intranasal administration is a delivery method that bypasses the BBB and can deliver large therapeutic molecules to the brain. Here, we propose a strategy to deliver ASOs to the brain using nanoparticle (NP) carriers we have developed which encapsulate ASOs, enhance their ability to cross cells membranes and penetrate the BBB. We will intranasally deliver these ASO NPs in HD mice to reduce mHTT in the brain. This approach represents a novel non-invasive means for improving delivery and distribution of ASOs into the brain, and advancing development of HD therapies.
Findings will be shared with the scientific public through publications and conference presentations, and to the general public and HD patients through educational seminars/workshops in our lab.