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

Koprich, James B.; Johnston, Tom H.; Reyes, Gabriela; Omana, Vanessa; Brotchie, Jonathan M.

doi:10.1371/journal.pone.0167235

Cited by 52 publications

(41 citation statements)

References 24 publications

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“…This magnitude of increase has functional benefit, being associated with a complete absence of behavioral deficit in the cylinder test and no increase in striatal dopamine turnover, a change considered to be compensating for reduced dopaminergic transmission. In the macaque model of PD that was recently developed (Koprich et al, 2016), AAV1/2-hourA53T-aSyn vectors were injected bilaterally into the SN. Over 4-8 months, this model showed an increase in striatal hA53T-aSyn, a decrease in TH 1ve cells in the SN (by ∼40%), and decreases in striatal dopamine and DAT (by ∼50%).…”

Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Howson¹,

Johnston²,

Ravenscroft³

et al. 2019

J Pharmacol Exp Ther

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Disease modification in Parkinson's disease (PD) is an unmet medical need. In the current study, we evaluated trehalose, a safe and well-tolerated disaccharide that has previously demonstrated efficacy in rodent models of neurodegenerative diseases, including PD. In a rat model of PD, based on delivery of adeno-associated virus serotype 1/2 containing the mutated human A53T a-synuclein gene (AAV1/2-hourA53T-aSyn) to the substantia nigra (SN), we showed that rats administered trehalose (2.67 g/kg per day, by mouth) for 6 weeks had less forelimb asymmetry (93% reduction) and higher striatal dopamine (54% increase) compared with rats receiving vehicle. In a pharmacokinetic study, we determined that efficacy was associated with plasma C max of 8900 ng/ml and area under the curve from time 0 to infinity (AUC 0-inf) of 11,136 hour×ng/ml. We then showed, in macaques, that oral administration of trehalose (2.67 g/kg per day) produced plasma exposures of similar magnitude, with plasma C max of 10,918 ng/ml and AUC 0-inf of 27,445 hour×ng/ml. In a macaque model of PD, also based on delivery of AAV1/2-hourA53T-aSyn to the SN, trehalose (2.67 g/kg per day, by mouth), administered for 142 days, produced higher striatal dopamine (by 39%) and dopamine transporter levels (by 50%), compared with macaques receiving vehicle. In neither model did trehalose treatment prevent loss of tyrosine hydroxylase (TH) positive (TH 1ve) cells in the SN or alter a-synuclein levels in the striatum. These studies demonstrated that trehalose reduces striatal dopaminergic deficits in a rodent and macaque model of synucleinopathy in PD. Furthermore, we have determined the pharmacokinetic parameters associated with efficacy, and thus defined exposures to target in future clinical trials.

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Section: Discussionmentioning

confidence: 99%

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Howson¹,

Johnston²,

Ravenscroft³

et al. 2019

J Pharmacol Exp Ther

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“…The cynomolgus monkey (Macaca fascicularis) is one of the most studied non-human primates (NHP) in neuroscience and medicine (6,7). Recent advances in transgenesis and genome-editing technologies have led to successful development of 5 new cynomolgus monkey models to study genetic human neurological disorders (8)(9)(10), making this species an excellent experimental NHP model for brain researchers.…”

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confidence: 99%

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Lei

Cheng

et al. 2020

Preprint

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Non-human primates (NHP) provide a unique opportunity to study human neurological diseases, yet detailed characterization of the cell types and transcriptional regulatory features in the NHP brain is lacking. We applied a combinatorial indexing assay, sci-ATAC-seq, as well as single-nuclei RNA-seq, to profile chromatin accessibility in 43,793 single cells and transcriptomics in 11,477 cells, respectively, from prefrontal cortex, primary motor cortex and the primary visual cortex of adult cynomolgus monkey Macaca fascularis. Integrative analysis of these two datasets, resolved regulatory elements and transcription factors that specify cell type distinctions, and discovered area-specific diversity in chromatin accessibility and gene expression within excitatory neurons. We also constructed the dynamic landscape of chromatin accessibility and gene expression of oligodendrocyte maturation to characterize adult remyelination. Furthermore, we identified cell type-specific enrichment of differentially spliced gene isoforms and disease-associated single nucleotide polymorphisms. Our datasets permit integrative exploration of complex regulatory dynamics in macaque brain tissue at single-cell resolution.

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“…They designed a rAAV1/2‐A53T ∝‐syn injected bilaterally in six cynomolgus macaques. ∝‐Synuclein was expressed in >85% of nigral neurons, the number of TH+ neurons decreased by 50%, and dopamine neurochemistry showed a 21%‐72% reduction according to the groups . Based on α‐syn delivery, these studies demonstrated the efficacy of this strategy to model PD.…”

Section: The Different Types Of Nhp Transgenic Modelsmentioning

confidence: 74%

Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate

Chansel‐Debordeaux

Bézard

2019

Anim Models and Exp Med

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Animal model is an essential tool in the life sciences research, notably in understanding the pathogenesis of the diseases and for further therapeutic intervention success. Rodents have been the most frequently used animals to model human disease since the establishment of gene manipulation technique. However, they remain inadequate to fully mimic the pathophysiology of human brain disease, partially due to huge differences between rodents and humans in terms of anatomy, brain function, and social behaviors. Nonhuman primates are more suitable in translational perspective. Thus, genetically modified animals have been generated to investigate neurologic and psychiatric disorders. The classical transgenesis technique is not efficient in that model; so, viral vector‐mediated transgene delivery and the new genome‐editing technologies have been promoted. In this review, we summarize some of the technical progress in the generation of an ad hoc animal model of brain diseases by gene delivery and real transgenic nonhuman primate.

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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

Cited by 52 publications

References 24 publications

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Beneficial Effects of Trehalose on Striatal Dopaminergic Deficits in Rodent and Primate Models of Synucleinopathy in Parkinson’s Disease

Spatially resolved gene regulatory and disease vulnerability map of the adult Macaque cortex

Local transgene expression and whole‐body transgenesis to model brain diseases in nonhuman primate

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