title: Systemic delivery of siRNA down regulates brain prion protein and ameliorates neuropathology in prion disorder.
abstract: One of the main challenges for neurodegenerative disorders that are principally incurable is the development of new therapeutic strategies, which raises important medical, scientific and societal issues. Creutzfeldt-Jakob diseases are rare neurodegenerative fatal disorders which today remain incurable. The objective of this study was to evaluate the efficacy of the down-regulation of the prion protein (PrP) expression using siRNA delivered by, a water-in-oil microemulsion, as a therapeutic candidate in a preclinical study. After 12 days rectal mucosa administration of Aonys/PrP-siRNA in mice, we observed a decrease of about 28% of the brain PrP(C) level. The effect of Aonys/PrP-siRNA was then evaluated on prion infected mice. Several mice presented a delay in the incubation and survival time compared to the control groups and a significant impact was observed on astrocyte reaction and neuronal survival in the PrP-siRNA treated groups. These results suggest that a new therapeutic scheme based an innovative delivery system of PrP-siRNA can be envisioned in prion disorders.
authors.affiliation: Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, diagnostic et thérapie cellulaire des affections neurodégénératives -Institut National de la Santé et de la Recherche Médicale Université Montpellier 1 U1040 Centre Hospitalo-Universitaire de Montpellier, Université Montpellier 1, Montpellier, France ; Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Lehmann
authors.affiliation: Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France.
authors.forename: Aroa
authors.initials: A
authors.lastname: Relano-Gines
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Resina
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Elsa
authors.initials: E
authors.lastname: Brillaud
authors.affiliation: Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France.
authors.forename: Danielle
authors.initials: D
authors.lastname: Casanova
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Vincent
authors.affiliation: Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Hamela
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Poupeau
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Laffont
authors.affiliation: Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, diagnostic et thérapie cellulaire des affections neurodégénératives -Institut National de la Santé et de la Recherche Médicale Université Montpellier 1 U1040 Centre Hospitalo-Universitaire de Montpellier, Université Montpellier 1, Montpellier, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Gabelle
authors.affiliation: Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, diagnostic et thérapie cellulaire des affections neurodégénératives -Institut National de la Santé et de la Recherche Médicale Université Montpellier 1 U1040 Centre Hospitalo-Universitaire de Montpellier, Université Montpellier 1, Montpellier, France.
authors.forename: Constance
authors.initials: C
authors.lastname: Delaby
authors.affiliation: Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Belondrade
authors.affiliation: Université Montpellier2, Montpellier, France.
authors.forename: Jacques-Damien
authors.initials: JD
authors.lastname: Arnaud
authors.affiliation: Université Montpellier2, Montpellier, France.
authors.forename: Maria-Teresa
authors.initials: MT
authors.lastname: Alvarez
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Maurel
authors.affiliation: Medesis Pharma SA, Baillargues, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Maurel
authors.affiliation: Institut de Médecine Régénératrice et de Biothérapie (I.M.R.B.), Physiopathologie, diagnostic et thérapie cellulaire des affections neurodégénératives -Institut National de la Santé et de la Recherche Médicale Université Montpellier 1 U1040 Centre Hospitalo-Universitaire de Montpellier, Université Montpellier 1, Montpellier, France ; Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Crozet
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000473:pathology*; D002452:Cell Count; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation; D005260:Female; D018014:Gene Transfer Techniques; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018621:PrPC Proteins / Q000378:metabolism*; D018620:PrPSc Proteins / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000378:metabolism*; D016019:Survival Analysis; D013997:Time Factors; D014617:Vacuoles / Q000378:metabolism
chemical_list: D016207:Cytokines; D018621:PrPC Proteins; D018620:PrPSc Proteins; D034741:RNA, Small Interfering