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Systemic exosomal delivery of shRNA minicircles prevents Parkinsonian pathology

Izco, M; Blesa, J; Schleef, M; Schmeer, M; Porcari, R; Al-Shawi, R; Ellmerich, S; ... Alvarez-Erviti, L; + view all (2019) Systemic exosomal delivery of shRNA minicircles prevents Parkinsonian pathology. Molecular Therapy 10.1016/j.ymthe.2019.08.010. (In press).

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Abstract

The development of new therapies to slow-down or halt Parkinson’s disease progression is a healthcare priority. A key pathological feature is the presence of alpha-synuclein aggregates and there is increasing evidence that alpha-synuclein propagation plays a central role in disease progression. Consequently the down-regulation of alpha-synuclein is a potential therapeutic target. As a chronic disease, the ideal treatment will be minimally invasive and effective in the long-term. Knockdown of gene expression has clear potential and siRNAs specific to alpha-synuclein have been designed, however the efficacy of siRNA treatment is limited by its short-term efficacy. To combat this we designed shRNA minicircles (shRNA-MC), with the potential for prolonged effectiveness, and used RVG-exosomes as vehicle for specific delivery into the brain. We optimized this system using transgenic mice expressing green fluorescent protein (GFP) and demonstrated its ability to down-regulate GFP protein expression in the brain for up to 6 weeks. RVG exosomes were used to deliver anti alpha-synuclein shRNA-MC therapy to the alpha-synuclein preformed fibrils induced model of parkinsonism. This therapy decreased alpha-synuclein aggregation, reduced the loss of dopaminergic neurones and improved the clinical symptoms. Our results confirm the therapeutic potential of shRNA-MC delivered by RVG-exosomes for long-term treatment of neurodegenerative diseases.

Type: Article
Title: Systemic exosomal delivery of shRNA minicircles prevents Parkinsonian pathology
DOI: 10.1016/j.ymthe.2019.08.010
Publisher version: https://doi.org/10.1016/j.ymthe.2019.08.010
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
URI: https://discovery.ucl.ac.uk/id/eprint/10081101
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