Objective: To develop novel therapeutic strategies for movement disorders by interfering with neuronal gene expression, PEI nanoparticle-mediated delivery of RNA was investigated in vivo.

Background: Parkinson’s disease (PD) is accompanied by altered gene expression levels in the brain. Recent studies support a role of regulatory non-coding RNAs, such as microRNAs, which silence a specific set of mRNAs at the post-transcriptional level. Upon their aberrant expression, they are likely involved in the pathophysiology of specific neuronal loss. Manipulation of neuronal gene expression is pivotal for understanding the function of proteins and the development of new therapeutic strategies. RNA interference strategies can be employed through the administration of small interfering RNAs (siRNA), which mediate the specific knockdown of a selected target gene. However, the main challenge is the delivery of these RNAs into the neurons of interest.

Methods: After their unilateral intracerebroventricular (ICV) injection we investigated the neuronal gene expression in the brain of mice overexpressing α-synuclein (Thy1-aSyn mice), a well characterized model of PD.

Results: PEI-complexed siRNA tagged with a fluorescence dye were ICV injected to track the localization and distribution. Five days later, fluorescent cells were visible throughout the brain, with the highest fluorescence intensity around the ventricles. Fluorescence was also observed in large cells of the lumbar spinal cord. Initial results demonstrate a 42.6% knockdown (p<0.05 student’s t-test, n=6) of human α-synuclein (SNCA) in the target structure striatum upon a single ICV injection of PEI-complexed specific siRNA compared to the control injection group (n=9).

Conclusions: Hence, our first results support the usability and efficacy of PEI nanoparticle-mediated delivery of siRNAs for rapidly and efficiently reducing the expression of a neuronal target gene of interest in the brain in vivo. This may allow the development of gene therapy strategies for the treatment of neurodegenerative diseases. Studies of toxicology and more detailed examinations of transfection efficiency, and the effect on protein levels in vivo and in vitro are ongoing.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/polyethylenimine-pei-nanoparticle-mediated-delivery-of-sirna-to-silence-neuronal-gene-expression-of-alpha-synuclein-in-a-mouse-model-of-parkinsons-disease/