I02 Systemic injection of exosomal sirna significantly reduced huntingtin expression in transgenic mice of huntington's disease. (September 2018)

• Record Type: Journal Article
• Authors: Wu, Tengteng; Yu, Mengchao; Zhang, Li; Chen, Xi; Pei, Zhong
• Is Part Of: Journal of neurology, neurosurgery and psychiatry. Volume 89(2018)Supplement 1
• Page Start: A88
• Page End: A89
• Publication Date: 2018-09
• Subjects: exosome -- siRNA -- protein lowering.; Neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; Psychiatry -- Periodicals; 616.8
• DOI: 10.1136/jnnp-2018-EHDN.238
• Languages: English
• ISSNs: 0022-3050

Abstract

Abstract : Background: Cell-derived exosomes have been demonstrated to be efficient carriers of small RNAs into brain tissue. However, the therapeutic effect of exosome-mediated siRNA has not been tested in Huntington's disease. Aims: To explore the therapeutic potential of exosome-mediated siRNA delivery in BACHD and N171-82Q mice model. Methods: We employed modified exosomes expressing the neuron-specific rabies viral glycoprotein (RVG) peptide loaded with siRNA targeting human huntingtin exon 1 (HuHtt) transcript. To determine the ability of modified exosomes selectively entering brain tissue, GFP-siRNA loaded exosome was administrated to GFP transgenic mice. HuHtt-siRNA RVG-exosomes was then intravenously injected to normal mice and BACHD and N171-82Q transgenic mice at 10 mg/kg every two days for 2 weeks. Performance of Rotarod test and Balance beam test was determine on N171-82Q mice post treatment. Results: RVG modified exosomes efficiently and specifically delivered siRNA into the mouse brain. siRNA-loaded RVG exosomes significantly reduced HuHtt mRNA and protein levels up to 46% and 54% respectively in transgenic animals. N171-82Q mice receiving RVG exosomes showed improvement on the performance of Rotarod test and Balance beam test. Conclusions: Our results demonstrate that RVG exosomes can efficiently transfer siRNA to the central nervous system and HuHtt-siRNA RVG-exosomes significantly reduce huntingtin expression. The present study indicates a therapeutic potential of HuHtt-siRNA RVG-exosomes in Huntington's disease.