1. 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
- Author
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James B. Koprich, Gabriela Reyes, Tom H. Johnston, Jonathan M. Brotchie, and Vanessa Omana
- Subjects
0301 basic medicine ,Parkinson's disease ,Epidemiology ,Dopamine ,Nigrostriatal pathway ,lcsh:Medicine ,Gene Expression ,Monkeys ,Disease Vectors ,Macaque ,Biochemistry ,chemistry.chemical_compound ,0302 clinical medicine ,Catecholamines ,Animal Cells ,Medicine and Health Sciences ,Amines ,lcsh:Science ,Mammals ,Neurons ,Multidisciplinary ,Movement Disorders ,biology ,Organic Compounds ,Dopaminergic ,Brain ,Neurochemistry ,Neurodegenerative Diseases ,Parkinson Disease ,Anatomy ,Neurotransmitters ,Dependovirus ,Substantia Nigra ,Chemistry ,medicine.anatomical_structure ,Neurology ,Vertebrates ,Physical Sciences ,alpha-Synuclein ,Female ,Cellular Types ,Neurochemicals ,Viral Vectors ,medicine.drug ,Research Article ,Primates ,Biogenic Amines ,Genetic Vectors ,Substantia nigra ,Microbiology ,Viral vector ,03 medical and health sciences ,biology.animal ,Virology ,Old World monkeys ,medicine ,Animals ,Humans ,Alpha-synuclein ,Biology and life sciences ,Dopaminergic Neurons ,lcsh:R ,Organic Chemistry ,Organisms ,Chemical Compounds ,Cell Biology ,Genetic Therapy ,medicine.disease ,Hormones ,Neostriatum ,Disease Models, Animal ,030104 developmental biology ,chemistry ,nervous system ,Cellular Neuroscience ,Amniotes ,Macaca ,lcsh:Q ,Neuroscience ,Dopaminergics ,030217 neurology & neurosurgery ,Viral Transmission and Infection - 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.
- Published
- 2016