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      Systemic Delivery of siRNA Down Regulates Brain Prion Protein and Ameliorates Neuropathology in Prion Disorder

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          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.

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          Depleting neuronal PrP in prion infection prevents disease and reverses spongiosis.

          Giovanna Mallucci, Andrew Dickinson, Jacqueline Linehan … (2003)
          The mechanisms involved in prion neurotoxicity are unclear, and therapies preventing accumulation of PrPSc, the disease-associated form of prion protein (PrP), do not significantly prolong survival in mice with central nervous system prion infection. We found that depleting endogenous neuronal PrPc in mice with established neuroinvasive prion infection reversed early spongiform change and prevented neuronal loss and progression to clinical disease. This occurred despite the accumulation of extraneuronal PrPSc to levels seen in terminally ill wild-type animals. Thus, the propagation of nonneuronal PrPSc is not pathogenic, but arresting the continued conversion of PrPc to PrPSc within neurons during scrapie infection prevents prion neurotoxicity.
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            Mice devoid of PrP are resistant to scrapie.

            A Aguzzi, C Weissmann, M Aguet … (1993)
            S.B. Prusiner proposed that the infectious agent of scraple, the prion, is PrPSc, a modified form of the normal host protein PrPC. Prn-p0/0 mice devoid of PrPC showed normal development and behavior. When inoculated with mouse scrapie prions, they remained free of scrapie symptoms for at least 13 months while wild-type controls all died within 6 months. Surprisingly, heterozygous Prn-p0/+ mice also showed enhanced resistance to scrapie. After introduction of Syrian hamster PrP transgenes, Prn-p0/0 mice became highly susceptible to hamster but not to mouse prions. These experiments show that PrPC, possibly at close to normal levels, is required for the usual susceptibility to scrapie and that lack of homology between incoming prions and the host's PrP genes retards disease.
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              Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL.

              Vassilis Zannis, Angeliki Chroni, Monty Krieger (2006)
              The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.
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                Author and article information

                Contributors
                Roberto Chiesa: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 14 February 2014
                Volume: 9
                Issue: 2
                Electronic Location Identifier: e88797
                Affiliations
                [1 ]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
                [2 ]Institut de Génétique Humaine, Centre National de la Recherche Scientifique- UPR1142, Montpellier, France
                [3 ]Medesis Pharma SA, Baillargues, France
                [4 ]Université Montpellier2, Montpellier, France
                Dulbecco Telethon Institute and Mario Negri Institute for Pharmacological Research, Italy
                Author notes

                Competing Interests: The author have read the journal’s policy and have the following conflicts: Medesis Pharma provided financial support for this collaborative research project. Sarah Resina, Elsa Brillaud, Charles Vincent, Sophie Poupeau, Jean-Claude Maurel and Patrick Maurel are employees of Medesis Pharma. Medesis Pharma was involved in experimental work and collection of raw data. Data analysis and writing of the article and conclusion were performed by the academic authors who have no link with Medesis Pharma. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: SL CC. Performed the experiments: SL CC ARG SR EB DC CV CH SP AG CD MB ML. Analyzed the data: SL CC ARG CD. Contributed reagents/materials/analysis tools: SL CC JDA MTA JCM PM. Wrote the paper: SL CC.

                Article
                Publisher ID: PONE-D-13-39878
                DOI: 10.1371/journal.pone.0088797
                PMC ID: 3925167
                PubMed ID: 24551164
                SO-VID: 39e6290f-c1fe-472c-bee3-86cf691618d3
                Copyright statement: Copyright @ 2014
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 28 September 2013
                Date accepted : 10 January 2014
                Page count
                Pages: 10
                Funding
                This work was supported by Medesis Pharma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Biochemistry
                Subject: Nucleic acids
                Subject: RNA
                Subject: RNA interference
                Subject: Drug discovery
                Subject: Biotechnology
                Subject: Drug discovery
                Subject: Genetics
                Subject: Gene expression
                Subject: RNA interference
                Subject: Molecular cell biology
                Subject: Gene expression
                Subject: RNA interference
                Subject: Medicine
                Subject: Drugs and devices
                Subject: Drug research and development
                Subject: Drug discovery
                Subject: Pharmacodynamics
                Subject: Infectious diseases
                Subject: Prion diseases
                Subject: Veterinary science
                Subject: Veterinary diseases
                Subject: Zoonotic diseases
                Subject: Prion diseases

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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