Selective suppression of α-Synuclein in monoaminergic neurons of mice by intranasal delivery of targeted small interfering RNA or antisense oligonucleotides: Potential therapy for Parkinson's disease
Póster presentado en: ACNP (American College of Neuropsychopharmacology) 52nd Annual Conference, celebrada del 8 al 12 de diciembre de 2013 en Hollywood, Florida (Estados Unidos)Abstract publicado en: Neuropsychopharmacology 38:S419-S420 (2013). ISSN: 0893-133X. eISSN: 1740-634X. DOI:10.1038/npp.2013.280α-Synuclein (α-Syn) appears to play a crucial role in the pathogenesis of several neurodegenerative disorders including Parkinson's disease (PD). The brains of Parkinson patients typically contain insoluble intracellular protein inclusions called Lewy bodies. Increased neuronal α-Syn levels represent a major component of Lewy bodies and therefore, the suppression of α-Syn expression provides a valid therapeutic target for PD. The goal of this study was to assess the ability of various small interfering RNA (siRNA) and antisense oligonucleotide (ASO) sequences directed against α-Syn to downregulate endogenous or overexpressed α-Syn mRNA levels in BE-M17 neuroblastoma cells. Moreover, we evaluated the feasibility of reducing α-Syn expression selectively in PD-vulnerable brain areas including substantia nigra pars compacta (SNc), ventral tegmental area (VTA), locus coeruleus (LC) and dorsal raphe nucleus (DR) of mice after the internalization of conjugated siRNA/ASO molecules into monoamine neurons following intranasal administration.
Conclusions: These results set the stage for the testing of these molecules as potential disease-modifying agents in neurotoxin-based and genetic models of PD linked to pathogenic increases in α-Syn. In this study we have characterized conjugated siRNA and ASO molecules that actively reduce endogenous α-Syn expression in vivo using the intranasal route to deliver directly siRNA/ASO into the brainPeer Reviewe
