Abstract
BackgroundThe early clinical trials using fetal ventral mesencephalic (VM) allografts in Parkinson’s disease (PD) patients have shown efficacy (albeit not in all cases) and have paved the way for further development of cell replacement therapy strategies in PD. The preclinical work that led to these clinical trials used allografts of fetal VM tissue placed into 6-OHDA lesioned rats, while the patients received similar allografts under cover of immunosuppression in an α-synuclein disease state. Thus developing models that more faithfully replicate the clinical scenario would be a useful tool for the translation of such cell-based therapies to the clinic.ResultsHere, we show that while providing functional recovery, transplantation of fetal dopamine neurons into the AAV-α-synuclein rat model of PD resulted in smaller-sized grafts as compared to similar grafts placed into the 6-OHDA-lesioned striatum. Additionally, we found that cyclosporin treatment was able to promote the survival of the transplanted cells in this allografted state and surprisingly also provided therapeutic benefit in sham-operated animals. We demonstrated that delayed cyclosporin treatment afforded neurorestoration in three complementary models of PD including the Thy1-α-synuclein transgenic mouse, a novel AAV-α-synuclein mouse model, and the MPTP mouse model. We then explored the mechanisms for this benefit of cyclosporin and found it was mediated by both cell-autonomous mechanisms and non-cell autonomous mechanisms.ConclusionThis study provides compelling evidence in favor for the use of immunosuppression in all grafted PD patients receiving cell replacement therapy, regardless of the immunological mismatch between donor and host cells, and also suggests that cyclosporine treatment itself may act as a disease-modifying therapy in all PD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-015-0263-6) contains supplementary material, which is available to authorized users.
Highlights
The progressive degeneration of nigral dopamine neurons is a central element in the pathophysiology of Parkinson’s disease (PD)
6-OHDA lesioned rats showed no sign of a motor deficit on the cylinder test 12 weeks after transplantation (P < 0.001 compared to 6-OHDA + sham group) [F3,42 = 28.33; 2-way ANOVA treatment × time interaction, P < 0.001] and elicited an overcompensation in the rotation test (−3.6 ± 1.3 turns/min; P < 0.001 compared to 6-OHDA + sham group) [F3,42 = 26.93; 2-way ANOVA treatment x time interaction, P < 0.001] (Fig. 1a-b)
Our results showed that immunosuppression had no effect on the speed of functional recovery [F2,32 = 1.10; 2-way ANOVA treatment x time interaction, P = 0.34] and did not statistically affect the magnitude of behavioral restoration (P = 0.08 compared to vehicle-treated animal at 12 weeks) (Fig. 3a), we saw the overcompensation on the rotational test (−4.3 ± 1.6 contralateral turns/min), similar to that we had observed in the 6-OHDA model (Fig. 1b)
Summary
The progressive degeneration of nigral dopamine neurons is a central element in the pathophysiology of Parkinson’s disease (PD). All the pre-clinical studies performed prior to the clinical trials were conducted in toxin-based models of PD obtained by either injection of 6hydroxydopamine (6-OHDA) in rats or 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) in nonhuman primates [4,5,6, 8, 51] These models are useful for looking at the restoration of the dopaminergic striatal innervation, they fail to replicate important pathological features including the development of the alpha-synuclein (α-synuclein) aggregation seen in the PD brain, which may influence the integration and long-term survival of the transplanted cells. Developing models that more faithfully replicate the clinical scenario would be a useful tool for the translation of such cell-based therapies to the clinic
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