Optimizing maturity and dose of iPSC-derived dopamine progenitor cell therapy for Parkinson’s disease (original) (raw)
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Cells
Parkinson’s disease (PD) is a neurodegenerative disorder associated with loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). One strategy for treating PD is transplantation of DA neuroblasts. Significant advances have been made in generating midbrain DA neurons from human pluripotent stem cells. Before these cells can be routinely used in clinical trials, extensive preclinical safety studies are required. One of the main issues to be addressed is the long-term therapeutic effectiveness of these cells. In most transplantation studies using human cells, the maturation of DA neurons has been analyzed over a relatively short period not exceeding 6 months. In present study, we generated midbrain DA neurons from human induced pluripotent stem cells (hiPSCs) and grafted these neurons into the SNpc in an animal model of PD. Graft survival and maturation were analyzed from 1 to 12 months post-transplantation (mpt). We observed long-term survival and functionality ...
Stem cells translational medicine, 2017
Recent reports have indicated human embryonic stem cells-derived midbrain dopamine (mDA) neurons as proper cell resources for use in Parkinson's disease (PD) therapy. Nevertheless, no detailed and systematic study has been conducted to identify which differentiation stages of mDA cells are most suitable for transplantation in PD therapy. Here, we transplanted three types of mDA cells, DA progenitors (differentiated in vitro for 16 days [D16]), immature DA neurons (D25), and DA neurons (D35), into PD mice and found that all three types of cells showed high viability and strong neuronal differentiation in vivo. Both D25 and D35 cells showed neuronal maturation and differentiation toward TH(+) cells and, accordingly, satisfactory behavioral functional recovery. However, transplanted D16 cells were less capable of producing functional recovery. These findings provide a valuable guideline for standardizing the differentiation stage of the transplantable cells used in clinical cell th...
2009
Dopaminergic (DA) grafts in rat models of Parkinson's disease (PD) have previously been derived from embryonic day (E) 14 grafts. Because there is an increasing interest in the restorative capacity of DA stem and progenitor cells, in the present study we examined the survival and early and late functional behavioral effects of DA progenitor cells derived from E12, E13, E14, and E15 grafts transplanted into rats with unilateral 6hydroxydopamin lesions. DA transplant-induced functional recovery was already observed in postural balancing reactions after 10 days and in stepping behavior after 13 days, that is, in spontaneous complex behaviors, and later, after 16 days, in the amphetamine-induced rotation test. Three distinct patterns of functional recovery could be observed at 6-9 weeks posttransplantation. First, behavioral improvements in drug-induced rotational asymmetry, stepping, and skilled forelimb behavior were directly related to DA neuron survival and TH-positive fiber reinnervation. Second, recovery in postural balancing reactions was closely related to a specific developmental time window of donor age, for example, only seen in E13 and E14 grafts. Finally, no functional graft effects were seen in the table lift test. Interestingly, DA neuron graft survival, TH-positive fiber outgrowth, and graft volume were significantly influenced by the developmental time window in which the DA progenitor cells were dissected from the ventral mesencephalon, that is, from E12, E13, E14, or E15 rat embryos. These data highlight the complexity of graft-host interactions and provide novel insights into the dynamics of DA progenitor graft-mediated functional recovery in animal models of Parkinson's disease. V V C 2009 Wiley-Liss, Inc.
Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson's Disease
2020
We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson's disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson's disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson's disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the Na...
Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease
Nature Medicine
Clinical studies of dopamine cell replacement therapies for Parkinson's disease (PD) go back more than 30 years. The outcomes using transplantation of human fetal ventral mesencephalic tissue (hfVM) have been variable, with some patients coming off their anti-PD treatment for many years, while other patients have not responded and/or developed significant side effects, including graftinduced dyskinesias. This led to a re-appraisal of how trials should best be done which resulted in a new EU funded allograft trial with fetal dopamine cells across several centres in Europe. This new trial, TRANSEURO 1 (NCT01898390); is an open label study in which patients were randomly selected for transplantation out of a larger observational cohort of patients with mild PD undergoing identical assessments. The TRANSEURO trial is currently ongoing, having completed both recruitment into a large multicentre observational study of younger onset early stage PD as well as transplantation of hfVM in 11 patients. While completion of TRANSEURO is not expected until 2021, we feel that sharing the rationale for the design of TRANSEURO, along with lessons we have learned along the way, can help to inform researchers and facilitate planning of human pluripotent stem cell-derived dopamine cell transplants for future clinical trials.
Proceedings of the National Academy of Sciences, 2010
Recent advances in deriving induced pluripotent stem (iPS) cells from patients offer new possibilities for biomedical research and clinical applications, as these cells could be used for autologous transplantation. We differentiated iPS cells from patients with Parkinson's disease (PD) into dopaminergic (DA) neurons and show that these DA neurons can be transplanted without signs of neurodegeneration into the adult rodent striatum. The PD patient iPS (PDiPS) cellderived DA neurons survived at high numbers, showed arborization, and mediated functional effects in an animal model of PD as determined by reduction of amphetamine-and apomorphine-induced rotational asymmetry, but only a few DA neurons projected into the host striatum at 16 wk after transplantation. We next applied FACS for the neural cell adhesion molecule NCAM on differentiated PDiPS cells before transplantation, which resulted in surviving DA neurons with functional effects on amphetamine-induced rotational asymmetry in a 6-OHDA animal model of PD. Morphologically, we found that PDiPS cell-derived non-DA neurons send axons along white matter tracts into specific close and remote gray matter target areas in the adult brain. Such findings establish the transplantation of human PDiPS cell-derived neurons as a long-term in vivo method to analyze potential disease-related changes in a physiological context. Our data also demonstrate proof of principle of survival and functional effects of PDiPS cell-derived DA neurons in an animal model of PD and encourage further development of differentiation protocols to enhance growth and function of implanted PDiPS cellderived DA neurons in regard to potential therapeutic applications. cell replacement therapy | dopaminergic neurons | Parkinson's disease | reprogramming | transplantation
Nature, 2011
Human pluripotent stem cells (hPSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of hPSCs into specialized cells such as spinal motoneurons 1 or midbrain dopamine (DA) neurons 2 has been achieved. However, the effective use of hPSCs for cell therapy has lagged behind. While mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease (PD) 3, 4 , DA neurons from human PSCs generally display poor in vivo performance 5 . There are also considerable safety concerns for hPSCs related to their potential for teratoma formation or neural overgrowth 6, 7