PET imaging of implanted human retinal pigment epithelial cells in the MPTP-induced primate model of Parkinson's disease

Doudet, Doris J.; Cornfeldt, Michael L.; Honey, Christopher R.; Schweikert, A.W.; Allen, Richard C.

doi:10.1016/j.expneurol.2004.06.009

Cited by 53 publications

(52 citation statements)

References 17 publications

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“…There is unequivocal evidence that hRPE-GM implants can survive without immunosuppression (17,18) as in fetal cell transplantation in PD patients (19). Increased 18 F-fluorodopa uptake and decreased 11 C-raclopride binding were reported in the implanted striatum after unilateral implant of hRPE-GM in monkeys, suggesting a dopaminergic mechanism (14). Despite sustained improvement in clinical motor scores over several years, these molecular markers are highly variable over the long term because of inherent compensatory modulation after therapy and disease progression in patients (20,21).…”

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confidence: 99%

“…Human retinal pigment epithelial (hRPE) cells of fetal origin, attached to gelatin microcarriers (GM; hrPE-GM) for enhanced survival, have been used as a potential therapy to reverse parkinsonian motor deficits in rodents (11,12), in monkeys (13,14), and, under the name Spheramine (Titan Pharmaceuticals, Inc.), in PD patients (15,16). There is unequivocal evidence that hRPE-GM implants can survive without immunosuppression (17,18) as in fetal cell transplantation in PD patients (19).…”

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confidence: 99%

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Modulation of Abnormal Metabolic Brain Networks by Experimental Therapies in a Nonhuman Primate Model of Parkinson Disease: An Application to Human Retinal Pigment Epithelial Cell Implantation

Peng

Flores

et al. 2016

J Nucl Med

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Abnormal covariance pattern of regional metabolism associated with Parkinson disease (PD) is modulated by dopaminergic pharmacotherapy. Using high-resolution 18 F-FDG PET and network analysis, we previously derived and validated a parkinsonism-related metabolic pattern (PRP) in nonhuman primate models of PD. It is currently not known whether this network is modulated by experimental therapeutics. In this study, we examined changes in network activity by striatal implantation of human levodopa-producing retinal pigment epithelial (hRPE) cells in parkinsonian macaques and evaluated the reproducibility of network activity in a small test-retest study. Methods: 18 F-FDG PET scans were acquired in 8 healthy macaques and 8 macaques with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced bilateral nigrostriatal dopaminergic lesions after unilateral putaminal implantation of hRPE cells or sham surgery. PRP activity was measured prospectively in all animals and in a subset of test-retest animals using a network quantification approach. Network activity and regional metabolic values were compared on a hemispheric basis between animal groups and treatment conditions. Results: All individual macaques showed clinical improvement after hRPE cell implantation compared with the sham surgery. PRP activity was elevated in the untreated MPTP hemispheres relative to those of the normal controls (P , 0.00005) but was reduced (P , 0.05) in the hRPE-implanted hemispheres. The modulation observed in network activity was supported by concurrent local and remote changes in regional glucose metabolism. PRP activity remained unchanged in the untreated MPTP hemispheres versus the sham-operated hemispheres. PRP activity was also stable (P $ 0.29) and correlated (R 2 $ 0.926; P , 0.00005) in the test-retest hemispheres. These findings were highly reproducible across several PRP topographies generated in multiple cohorts of parkinsonian and healthy macaques. Conclusion: We have demonstrated long-term therapeutic effects of hRPE cell implantation in nonhuman primate models of PD. The implantation of such levodopa-producing cells can concurrently decrease the elevated metabolic network activity in parkinsonian brains on an individual basis. These results parallel the analogous findings reported in patients with PD undergoing levodopa therapy and other symptomatic interventions. With further validation in large samples, 18 F-FDG PET imaging with network analysis may provide a viable biomarker for assessing treatment response in animal models of PD after experimental therapies. The motor clinical manifestations of Parkinson disease (PD) are attributed chiefly to progressive loss of nigrostriatal dopaminergic neurons. This degenerative process causes a deficiency of endogenous dopamine, leading to impairment in the cortico-striatothalamo-cortical motor circuitry. 18 F-FDG PET has been widely used to study functional abnormality in this circuitry. Motor features of PD are associated with an abnormal metabolic brain network (i.e., Parkins...

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confidence: 99%

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confidence: 99%

Modulation of Abnormal Metabolic Brain Networks by Experimental Therapies in a Nonhuman Primate Model of Parkinson Disease: An Application to Human Retinal Pigment Epithelial Cell Implantation

Peng

Flores

et al. 2016

J Nucl Med

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“…An increased survival of hRPE cells, without immunosuppression, and long term functional improvements were observed, although chronic inflammation was reported at later timepoints (5 months) (Flores et al, 2007). These microcarriers have also been implanted in the brain of hemi-parkinsonian monkeys and resulted in long term cell survival and functional improvements at 18 months (Doudet et al, 2004). As expected, hRPE cells unattached to microcarriers did not survive well in the brain, and did not produce a lasting therapeutic effect in various PD animal models.…”

Section: Cell Adhesion On Particulate Scaffoldsmentioning

confidence: 98%

Advances in the Combined Use of Adult Cell Therapy and Scaffolds for Brain Tissue Engineering

Garbayo¹,

Delcroix²,

Schiller³

et al. 2011

Tissue Engineering for Tissue and Organ Regeneration

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“…They can be easily expanded in culture and stored as frozen stocks, allowing extensive characterization and testing before transplantation. hRPE cells attached to gelatin microcarriers (GM) show enhanced survival and improve motor deficits after striatal grafts in rodents (Subramanian et al, 2002;Cepeda et al, 2007) and in NHP models of PD (Watts et al, 2003;Doudet et al, 2004). RPE-GM are currently used in human PD patients under the name of Spheramine (Titan Pharmaceuticals, Inc.).…”

Section: Other Cell Typesmentioning

confidence: 99%

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

Wianny

Vezoli

2017

Primate Biol.

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Abstract. In order to calibrate stem cell exploitation for cellular therapy in neurodegenerative diseases, fundamental and preclinical research in NHP (nonhuman primate) models is crucial. Indeed, it is consensually recognized that it is not possible to directly extrapolate results obtained in rodent models to human patients. A large diversity of neurological pathologies should benefit from cellular therapy based on neural differentiation of stem cells. In the context of this special issue of Primate Biology on NHP stem cells, we describe past and recent advances on cell replacement in the NHP model of Parkinson's disease (PD). From the different grafting procedures to the various cell types transplanted, we review here diverse approaches for cell-replacement therapy and their related therapeutic potential on behavior and function in the NHP model of PD.

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PET imaging of implanted human retinal pigment epithelial cells in the MPTP-induced primate model of Parkinson's disease

Cited by 53 publications

References 17 publications

Modulation of Abnormal Metabolic Brain Networks by Experimental Therapies in a Nonhuman Primate Model of Parkinson Disease: An Application to Human Retinal Pigment Epithelial Cell Implantation

Modulation of Abnormal Metabolic Brain Networks by Experimental Therapies in a Nonhuman Primate Model of Parkinson Disease: An Application to Human Retinal Pigment Epithelial Cell Implantation

Advances in the Combined Use of Adult Cell Therapy and Scaffolds for Brain Tissue Engineering

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

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