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
, 27
(12)
pp. 2111-2122.
10.1016/j.ymthe.2019.08.010.
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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.
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