title: Systemic exosomal siRNA delivery reduced alpha-synuclein aggregates in brains of transgenic mice.
abstract: Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions.
authors.affiliation: Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Cooper
authors.forename: P B Oscar
authors.initials: PB
authors.lastname: Wiklander
authors.forename: Joel Z
authors.initials: JZ
authors.lastname: Nordin
authors.forename: Raya
authors.initials: R
authors.lastname: Al-Shawi
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wood
authors.forename: Mansi
authors.initials: M
authors.lastname: Vithlani
authors.forename: Anthony H V
authors.initials: AH
authors.lastname: Schapira
authors.forename: J Paul
authors.initials: JP
authors.lastname: Simons
authors.forename: Samir
authors.initials: S
authors.lastname: El-Andaloussi
authors.forename: Lydia
authors.initials: L
authors.lastname: Alvarez-Erviti
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000378:metabolism; D055354:Exosomes / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000502:physiology; D005822:Genetic Vectors / Q000235:genetics; D006023:Glycoproteins / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D013997:Time Factors; D014162:Transfection; D014764:Viral Proteins / Q000008:administration & dosage / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics* / Q000378:metabolism*
chemical_list: D006023:Glycoproteins; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014764:Viral Proteins; D051844:alpha-Synuclein; C583075:rabies virus glycoprotein peptide
keywords: RVG-exosomes; siRNA; transgenic mice; α-Syn
references.citation: Nat Cell Biol. 2002 Feb;4(2):160-4
references.pmid: 11813001
references.citation: Science. 2003 Oct 31;302(5646):841
references.pmid: 14593171
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17204-9
references.pmid: 17940007
references.citation: Cold Spring Harb Perspect Med. 2012 Apr;2(4):a009431
references.pmid: 22474617
references.citation: Nat Biotechnol. 2011 Apr;29(4):341-5
references.pmid: 21423189
references.citation: Neurobiol Aging. 2003 Mar-Apr;24(2):197-211
references.pmid: 12498954
references.citation: Nat Cell Biol. 2007 Jun;9(6):654-9
references.pmid: 17486113
references.citation: Neuron. 2010 Jun 10;66(5):646-61
references.pmid: 20547124
references.citation: Neuron. 2006 Oct 5;52(1):33-8
references.pmid: 17015225
references.citation: Mol Neurodegener. 2008 Nov 01;3:19
references.pmid: 18976489
references.citation: J Biol Chem. 2006 Oct 6;281(40):29739-52
references.pmid: 16847063
references.citation: Science. 2012 Nov 16;338(6109):949-53
references.pmid: 23161999
references.citation: Ann Neurol. 2014 Mar;75(3):351-62
references.pmid: 24243558
references.citation: J Neurosci. 2007 Aug 22;27(34):9220-32
references.pmid: 17715357
references.citation: Lancet. 2004 Sep 25-Oct 1;364(9440):1167-9
references.pmid: 15451224
references.citation: Hum Mol Genet. 2009 Mar 1;18(5):872-87
references.pmid: 19074459
references.citation: J Neurosci. 2004 Oct 20;24(42):9434-40
references.pmid: 15496679
references.citation: Neuron. 2000 Jan;25(1):239-52
references.pmid: 10707987
references.citation: Cell Death Dis. 2013 Mar 14;4:e545
references.pmid: 23492776
references.citation: Pharm Res. 2009 May;26(5):1059-63
references.pmid: 19104914
references.citation: Trends Biotechnol. 1997 Oct;15(10):410-8
references.pmid: 9351285
references.citation: Biochim Biophys Acta. 2009 Jul;1792(7):730-40
references.pmid: 18718530
references.citation: Cell. 2000 Mar 31;101(1):57-66
references.pmid: 10778856
references.citation: Neurobiol Dis. 2013 Aug;56:47-58
references.pmid: 23567651