title: 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.
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.
authors.affiliation: Atuka Inc., Toronto, Canada.|Krembil Research Institute, University Health Network, Toronto, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Koprich
authors.affiliation: Atuka Inc., Toronto, Canada.|Krembil Research Institute, University Health Network, Toronto, Canada.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, Canada.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Reyes
authors.affiliation: Krembil Research Institute, University Health Network, Toronto, Canada.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Omana
authors.affiliation: Atuka Inc., Toronto, Canada.|Krembil Research Institute, University Health Network, Toronto, Canada.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008251:Macaca; D017072:Neostriatum / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051844:alpha-Synuclein / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein