Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson’s Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque
Identifieur interne : 000157 ( Main/Exploration ); précédent : 000156; suivant : 000158Towards a Non-Human Primate Model of Alpha-Synucleinopathy for Development of Therapeutics for Parkinson’s Disease: Optimization of AAV1/2 Delivery Parameters to Drive Sustained Expression of Alpha Synuclein and Dopaminergic Degeneration in Macaque
Auteurs : James B. Koprich [Canada] ; Tom H. Johnston [Canada] ; Gabriela Reyes [Canada] ; Vanessa Omana [Canada] ; Jonathan M. Brotchie [Canada]Source :
- PLoS ONE [ 1932-6203 ] ; 2016.
Abstract
Recent failures in clinical trials for disease modification in Parkinson’s disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 1012 gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.
Url:
DOI: 10.1371/journal.pone.0167235
PubMed: 27902767
PubMed Central: 5130249
Affiliations:
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Koprich</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Atuka Inc., Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Atuka Inc., Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Krembil Research Institute, University Health Network, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Krembil Research Institute, University Health Network, Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation></author><author><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Atuka Inc., Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Atuka Inc., Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Krembil Research Institute, University Health Network, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Krembil Research Institute, University Health Network, Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation></author><author><name sortKey="Reyes, Gabriela" sort="Reyes, Gabriela" uniqKey="Reyes G" first="Gabriela" last="Reyes">Gabriela Reyes</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Krembil Research Institute, University Health Network, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Krembil Research Institute, University Health Network, Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation></author><author><name sortKey="Omana, Vanessa" sort="Omana, Vanessa" uniqKey="Omana V" first="Vanessa" last="Omana">Vanessa Omana</name><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Krembil Research Institute, University Health Network, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Krembil Research Institute, University Health Network, Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation></author><author><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><affiliation wicri:level="1"><nlm:aff id="aff001"><addr-line>Atuka Inc., Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Atuka Inc., Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation><affiliation wicri:level="1"><nlm:aff id="aff002"><addr-line>Krembil Research Institute, University Health Network, Toronto, Canada</addr-line></nlm:aff><country xml:lang="fr">Canada</country><wicri:regionArea>Krembil Research Institute, University Health Network, Toronto</wicri:regionArea><wicri:noRegion>Toronto</wicri:noRegion></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2016">2016</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Recent failures in clinical trials for disease modification in Parkinson’s disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 10<sup>12</sup> gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Tagliafierro, L" uniqKey="Tagliafierro L">L Tagliafierro</name></author><author><name sortKey="Chiba Falek, O" uniqKey="Chiba Falek O">O Chiba-Falek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Xu, W" uniqKey="Xu W">W Xu</name></author><author><name sortKey="Tan, L" uniqKey="Tan L">L Tan</name></author><author><name sortKey="Yu, Jt" uniqKey="Yu J">JT Yu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ozansoy, M" uniqKey="Ozansoy M">M Ozansoy</name></author><author><name sortKey="Basak, An" uniqKey="Basak A">AN Basak</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bellucci, A" uniqKey="Bellucci A">A Bellucci</name></author><author><name 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sortKey="Guo, X" uniqKey="Guo X">X Guo</name></author><author><name sortKey="Yin, P" uniqKey="Yin P">P Yin</name></author><author><name sortKey="Gao, J" uniqKey="Gao J">J Gao</name></author></analytic></biblStruct></listBibl></div1></back></TEI><affiliations><list><country><li>Canada</li></country></list><tree><country name="Canada"><noRegion><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name></noRegion><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Brotchie, Jonathan M" sort="Brotchie, Jonathan M" uniqKey="Brotchie J" first="Jonathan M." last="Brotchie">Jonathan M. Brotchie</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><name sortKey="Johnston, Tom H" sort="Johnston, Tom H" uniqKey="Johnston T" first="Tom H." last="Johnston">Tom H. Johnston</name><name sortKey="Koprich, James B" sort="Koprich, James B" uniqKey="Koprich J" first="James B." last="Koprich">James B. Koprich</name><name sortKey="Omana, Vanessa" sort="Omana, Vanessa" uniqKey="Omana V" first="Vanessa" last="Omana">Vanessa Omana</name><name sortKey="Reyes, Gabriela" sort="Reyes, Gabriela" uniqKey="Reyes G" first="Gabriela" last="Reyes">Gabriela Reyes</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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