Modeling Parkinson's disease in monkeys for translational studies, a critical analysis

Abstract

The non-human primate MPTP model of Parkinson’s disease is an essential tool for translational studies. However, the currently used methodologies to produce parkinsonian monkeys do not follow unified criteria, and the applied models may often fall short of reproducing the characteristics of patients in clinical trials. Pooling of data from the parkinsonian monkeys produced in our Centers provided the opportunity to evaluate thoroughly the behavioral outcomes that may be considered for appropriate modeling in preclinical studies. We reviewed records from 108 macaques including rhesus and cynomolgus species used to model moderate to advanced parkinsonism with systemic MPTP treatment. The attained motor disability and the development of levodopa-induced dyskinesias, as primary outcomes, and the occurrence of clinical complications and instability of symptoms were all analyzed for correlations with the parameters of MPTP administration and for estimation of sample sizes. Results showed that frequently the MPTP-treated macaque can recapitulate the phenotype of patients entering clinical trials, but to produce this model consistently it is important to adapt the MPTP exposure tightly according to individual animal responses. For studies of reduced animal numbers it is also important to produce stable models, and stability of parkinsonism in macaques critically depends on reaching “marked” motor disability. The analyzed data also led to put forward recommendations for successfully producing the primate MPTP model of Parkinson’s disease for translational studies.

Enhancement of Striatal Dopaminergic Function Following Autologous Neural Cell Ecosystems (ANCE) Transplantation in a Non-Human Primate Model of Parkinson’s Disease

“…On a behavioral point of view, all four animals were differently affected by the MPTP lesion (Figure 2; based on the semi-quantitative Schneider score), confirming the large inter-individual variability previously reported in the literature and representing an obvious limitation of the non-human primate MPTP model [34,[46][47][48]. Such observed inter-individual variability places the present experimental model within the standards in the field (animal PD models).…”

“…One may speculate that such sprouting of residual dopaminergic projection contributes to functional recovery, in cooperation with non-dopaminergic compensatory mechanisms [44,45]. The observation in monkey Mk-LY of a modest decrease of striatal 18F-DOPA uptake post-MPTP lesion (17%) may possibly be interpreted as a resistance to MPTP [46], at least to some extent.…”

Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies

“…Specifically, in the context of hESC-based therapy for PD, preclinical testing of functional stability will likely depend on the stability of parkinsonism in nonhuman primate models [51].…”

Transplantation in the nonhuman primate MPTP model of Parkinson's disease: update and perspectives

“…The low-dose MPTP monkey model (Bezard et al, 1997) is the model of choice for translational study because it presents a parkinsonian syndrome characterized by all critical aspects of PD, including a slow progressive evolution of symptoms, e.g., it replicates the typical motor symptoms used for primary clinical diagnosis of parkinsonism with response to classical DA therapy (Stephenson et al, 2005), characteristic pattern of nigrostriatal denervation observed in PD patients (Gibb and Lees, 1991;Perez-Otano et al, 1994), early and long-lasting non-motor symptoms (Poewe, 2008;Vezoli et al, 2011;Fifel et al, 2014;Swallow et al, 2016), and increased α-synuclein expression in the pigmented cells of the SN (substantia nigra; Purisai et al, 2005). However, even if those inclusion bodies appears in the same sites as for Lewy bodies in PD, e.g., SN, they do not express typical Lewy body features as found in human PD patients (Forno et al, 1993).…”

“…Here we focus on preclinical investigations done in the gold standard NHP MPTP model (Emborg, 2007;Potts et al, 2014). We provide a non-exhaustive review of different procedures using transplantation of various cell sources as a therapeutic approach in the NHP MPTP model of PD and provide an update on linked therapeutic behavioral and functional outcomes.…”