title: Intravenous administration of brain-targeted stable nucleic acid lipid particles alleviates Machado-Joseph disease neurological phenotype.
abstract: Others and we showed that RNA interference holds great promise for the treatment of dominantly inherited neurodegenerative disorders such as Machado-Joseph disease (MJD), for which there is no available treatment. However, successful experiments involved intracranial administration of viral vectors and there is a need for a safer and less invasive procedure. In this work, we successfully generated stable nucleic acid lipid particles (SNALPs), incorporating a short peptide derived from rabies virus glycoprotein (RVG-9r) and encapsulating small interfering RNAs (siRNAs), which can target mutant ataxin-3. The developed formulation exhibited important features that make it adequate for systemic administration: high encapsulation efficiency of siRNAs, ability to protect the encapsulated siRNAs, appropriate and homogeneous particle size distribution. Following optimization of the formulation and in vitro validation of its efficacy to silence the MJD-causing protein - mutant ataxin-3 - in neuronal cells, in vivo experiments showed that intravenous administration of RVG-9r-targeted SNALPs efficiently silenced mutant ataxin-3 reducing neuropathology and motor behavior deficits in two mouse models of MJD. To our knowledge, this is the first report showing beneficial impact of a non-viral gene silencing strategy in MJD and the first time that a non-invasive systemic administration proved to be beneficial on a polyglutamine disorder. Our study opens new avenues towards MJD therapy that can also be applied to other neurodegenerative diseases linked to the production of pathogenic proteins.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: Mariana
authors.initials: M
authors.lastname: Conceição
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Liliana
authors.initials: L
authors.lastname: Mendonça
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Clévio
authors.initials: C
authors.lastname: Nóbrega
authors.affiliation: IBILI - Institute of Biomedical Research in Light and Image, Faculty of Medicine, University of Coimbra, 3000-354 Coimbra, Portugal.
authors.forename: Célia
authors.initials: C
authors.lastname: Gomes
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Costa
authors.affiliation: Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal.
authors.forename: João Nuno
authors.initials: JN
authors.lastname: Moreira
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Lima
authors.affiliation: Center of Excellence in Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: N
authors.initials: N
authors.lastname: Manjunath
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal; Faculty of Pharmacy, University of Coimbra, 3000-548 Coimbra, Portugal. Electronic address: luispa@cnc.uc.pt.
authors.forename: Luís
authors.initials: L
authors.lastname: Pereira de Almeida
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D004355:Drug Stability; D020868:Gene Silencing; D007275:Injections, Intravenous; D008055:Lipids / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry; D017827:Machado-Joseph Disease / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009696:Nucleic Acids / Q000008:administration & dosage*; D010316:Particle Size; D010641:Phenotype; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D008055:Lipids; D008081:Liposomes; D009696:Nucleic Acids; D034741:RNA, Small Interfering
keywords: Behavioral assessment; Brain-targeted SNALPs; Intravenous administration; Nanoparticles; Near infrared imaging; Neurodegeneration; siRNA delivery