Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial

Gross, Robert E.; Watts, R. L.; Hauser, Robert A.; Bakay, Roy A.E.; Reichmann, Heinz; Kummer, Rüdiger von; Ondo, William G.; Reissig, Elke; Eisner, Wilhelm; Steiner-Schulze, Heike; Siedentop, Harald; Fichte, K; Hong, Walter; Cornfeldt, Michael L.; Beebe, Katherine; Sandbrink, Rupert

doi:10.1016/s1474-4422(11)70097-7

Cited by 149 publications

(130 citation statements)

References 38 publications

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“…The parkinsonian animals were evaluated before and 6-48 mo after unilateral striatal implantation (Fig. 1A) and rated as mild moderate (n 5 7) or moderately severe (n 5 1) at the time of imaging (motor score, 11.9 6 5.1; range, [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23].…”

Section: Characteristics Of Macaquesmentioning

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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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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Section: Characteristics Of Macaquesmentioning

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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“…In 2011, the results of the first randomized, double-blind, placebo-controlled trial of RPE cell transplantation in PD patients showed that hRPE cells provided no antiparkinsonian benefits over sham surgery (Gross et al, 2011). Optimal therapeutic benefit could be reached after administration of low doses of levodopa.…”

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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“…Similarly, Guyuron and colleagues used a skin incision to expose superficial nerves and muscles, which were cut during the active surgery but, in the placebo group, the integrity of these structures was maintained 33 . Trials investigating transplantation of dopaminergic neurones as a treatment for Parkinson’s disease not only required skin incision but also burr holes in the skull 34, 35 .…”

Section: Strategies Used To Maintain Blinding In Interventional Placementioning

confidence: 99%

“…Many trials specifically stated that the duration of procedure in the surgical and control arms were matched, either by immitating the elements of the surgical procedure or by keeping all patients in the operation room for the same duration of time 34, 38, 45, 47, 48, 60, 61 . However, in some trials, the placebo procedure was shortened in comparison to the actual surgery because it was believed it would have been ethically unacceptable to prolong the placebo intervention 49, 55 .…”

Section: Strategies Used To Maintain Blinding In Interventional Placementioning

confidence: 99%

Blinding in trials of interventional procedures is possible and worthwhile

2017

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In this paper, we have used evidence from our earlier review of surgical randomised controlled trials with a placebo arm to show that blinding in trials of interventional procedures is feasible, and that many creative methods can be used to make the active and the placebo procedure as similar as possible. We give examples of ingenious strategies used to simulate the active procedure and make the placebo control indistinguishable from the active treatment. We discuss why it is important to blind of patients, assessors, and caregivers and the types of bias that may occur in interventional trials. Finally, we describe the benefits of blinding, from the obvious ones such as avoiding bias, as well as less evident benefits such as avoiding patient drop out in the control arm.

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Intrastriatal transplantation of microcarrier-bound human retinal pigment epithelial cells versus sham surgery in patients with advanced Parkinson's disease: a double-blind, randomised, controlled trial

Cited by 149 publications

References 38 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

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

Blinding in trials of interventional procedures is possible and worthwhile

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