Gene

Cell biology

Neuroscience

Biology

Gene delivery

Blood–brain barrier

Huntington's disease

Cancer research

Biochemistry

Small interfering RNA

Transfection

Gene silencing

Huntingtin

Huntingtin Protein

In vitro

RNA interference

Central nervous system

Pharmacology

Medicine

Chemistry

Disease

Pathology

European Journal of Pharmaceutics and Biopharmaceutics

Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene, leading to a toxic version of the HTT protein. There are currently no disease-modifying therapies available. In this scenario, gene-based treatments for HD aimed at lowering HTT levels have become one of the most promising emerging therapeutic options. To date, however, promising results have only been achieved following direct intrathecal or intracranial injections designed to circumvent the blood-brain barrier (BBB). Consequently, efforts to develop less invasive delivery platforms are highly desirable. Here, we described a novel delivery system based on modified cyclodextrin nanoparticles (CDs) loaded with small interfering RNAs (siRNAs) targeting HTT andcomplexed with the rabies virus glycoprotein(RVG), a BBB-shuttle peptide. Results using an in vitro BBB model, indicate the formulation successfully crosses the brain endothelial cells, releases the encapsulated siRNAs into the cytoplasm of neuronal cells, and mediates downregulation of HTT. In conclusion, the CD platform is a promising option for delivery of siRNA-based therapeutics for HD with wider potential to treat other diseases with a genetically validated target in the central nervous system.

Modified cyclodextrin-based nanoparticles mediated delivery of siRNA for huntingtin gene silencing across an in vitro BBB model