Godinho, BMDC,Ogier, JR,Darcy, R,Driscoll, CM,Cryan, JF

2013

January

Molecular Pharmaceutics

Self-assembling Modified beta-Cyclodextrin Nanoparticles as Neuronal siRNA Delivery Vectors: Focus on Huntington's Disease

Validated

()

nonviral vectors gene therapy rotarod neurodegenerative disease RNAi CNS delivery SMALL INTERFERING RNA CHEMICALLY-MODIFIED SIRNA ADULT-MOUSE BRAIN TARGETED NANOPARTICLES MUTANT HUNTINGTIN MAMMALIAN NEURONS GENE KNOCKDOWN RAT MODEL TRANSFECTION

10

640

649

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disease caused by the expression of a toxic Huntingtin (HTT) protein. The use of short interfering RNAs (siRNAs) to silence the mutant protein is one of the most promising therapeutic strategies under investigation. The biggest caveat to siRNA-based approaches is the lack of efficient and nontoxic delivery vectors for siRNA delivery to the central nervous system. In this study, we investigated the potential of modified amphiphilic beta-cyclodextrins (CDs), oligosaccharide-based molecules, as novel siRNA neuronal carriers. We show that CDs formed nanosize particles which were stable in artificial cerebrospinal fluid. Moreover, these complexes were able to reduce the expression of the HTT gene in rat striatal cells (ST14A-HTT120Q) and in human HD primary fibroblasts. Only limited toxicity was observed with CD.siRNA nanoparticles in any of the in vitro models used. Sustained knockdown effects were observed in the striatum of the R6/2 mouse model of HD after single direct injections of CD.siRNA nanoparticles. Repeated brain injections of CD.siRNA complexes resulted in selective alleviation of motor deficits in this mouse model. Together these data support the utility of modified beta-CDs as efficient and safe siRNA delivery vectors for RNAi-based therapies for neuropsychiatric and neurodegenerative disorders.

DOI 10.1021/mp3003946