Cell-based therapies in Parkinson’s disease

Greene, Paul

doi:10.1007/s11910-009-0044-3

Cited by 15 publications

(5 citation statements)

References 48 publications

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“…Potential sources for cell replacement have included fetal ventral mesencephalon tissue and various stem cell types that can differentiate into dopaminergic neurons. Numerous experimental replacement therapies have been examined in preclinical animal models and in clinical trials (reviewed in [95,96]). MSCs have also been examined in animal models of PD, for their neurorestorative effects and as delivery vehicles for production of additional factors.…”

Section: Parkinson's Diseasementioning

confidence: 99%

Mesenchymal stem cells for the treatment of neurodegenerative disease

et al. 2010

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Mesenchymal stem cells/marrow stromal cells (MSCs) present a promising tool for cell therapy, and are currently being tested in US FDA-approved clinical trials for myocardial infarction, stroke, meniscus injury, limb ischemia, graft-versus-host disease and autoimmune disorders. They have been extensively tested and proven effective in preclinical studies for these and many other disorders. There is currently a great deal of interest in the use of MSCs to treat neurodegenerative diseases, in particular for those that are fatal and difficult to treat, such as Huntington's disease and amyotrophic lateral sclerosis. Proposed regenerative approaches to neurological diseases using MSCs include cell therapies in which cells are delivered via intracerebral or intrathecal injection. Upon transplantation into the brain, MSCs promote endogenous neuronal growth, decrease apoptosis, reduce levels of free radicals, encourage synaptic connection from damaged neurons and regulate inflammation, primarily through paracrine actions. MSCs transplanted into the brain have been demonstrated to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons. Therapies will capitalize on the innate trophic support from MSCs or on augmented growth factor support, such as delivering brain-derived neurotrophic factor or glial-derived neurotrophic factor into the brain to support injured neurons, using genetically engineered MSCs as the delivery vehicles. Clinical trials for MSC injection into the CNS to treat traumatic brain injury and stroke are currently ongoing. The current data in support of applying MSC-based cellular therapies to the treatment of neurodegenerative disorders are discussed.

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Section: Parkinson's Diseasementioning

confidence: 99%

Mesenchymal stem cells for the treatment of neurodegenerative disease

et al. 2010

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“…After many encouraging open-label studies of fetal cell transplantation for PD, three randomized, double-blind, placebo-controlled studies found no net benefit. In addition, patients in two of the studies developed dyskinesias that persisted despite reductions in medication (87). Interestingly, recent reports have shown that as early as 14 years after transplantation into the striatum of individuals with PD, grafted nigral neurons are found to have Lewy body-like inclusions that stained positively for α -synuclein and ubiquitin and to have reduced immunostaining for DA transporter (112, 126).…”

Section: Npc Transplants and Brain Repairmentioning

confidence: 99%

Brain Regeneration in Physiology and Pathology: The Immune Signature Driving Therapeutic Plasticity of Neural Stem Cells

Martino

Pluchino

Bonfanti

et al. 2011

Physiological Reviews

205

196

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Regenerative processes occurring under physiological (maintenance) and pathological (reparative) conditions are a fundamental part of life and vary greatly among different species, individuals, and tissues. Physiological regeneration occurs naturally as a consequence of normal cell erosion, or as an inevitable outcome of any biological process aiming at the restoration of homeostasis. Reparative regeneration occurs as a consequence of tissue damage. Although the central nervous system (CNS) has been considered for years as a "perennial" tissue, it has recently become clear that both physiological and reparative regeneration occur also within the CNS to sustain tissue homeostasis and repair. Proliferation and differentiation of neural stem/progenitor cells (NPCs) residing within the healthy CNS, or surviving injury, are considered crucial in sustaining these processes. Thus a large number of experimental stem cell-based transplantation systems for CNS repair have recently been established. The results suggest that transplanted NPCs promote tissue repair not only via cell replacement but also through their local contribution to changes in the diseased tissue milieu. This review focuses on the remarkable plasticity of endogenous and exogenous (transplanted) NPCs in promoting repair. Special attention will be given to the cross-talk existing between NPCs and CNS-resident microglia as well as CNS-infiltrating immune cells from the circulation, as a crucial event sustaining NPC-mediated neuroprotection. Finally, we will propose the concept of the context-dependent potency of transplanted NPCs (therapeutic plasticity) to exert multiple therapeutic actions, such as cell replacement, neurotrophic support, and immunomodulation, in CNS repair.

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“…Although these clinical trials clearly indicate room for improvement to enhance graft function as well as reduce unwarranted dyskinetic side effects, they also indicate positive short‐term clinical benefit in a subset of patients similar to open‐label trials and highlight potential problems to tackle, understand, and eventually resolve in future studies (reviews150–154). Specifically, a consensus must come to a standardization for method of dissection, age and number of donor fetuses, length of tissue incubation postisolation, as well as the target site, number of sites to graft, and a variety of other surgical parameters with clinical relevance reviewed elsewhere 45,155.…”

Section: Neuronal Transplantation In Parkinson's Diseasementioning

confidence: 99%

Cell Transplantation and Gene Therapy in Parkinson's Disease

Wakeman

Dodiya

Kordower

2011

Mount Sinai J Medicine

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Parkinson's disease is a progressive neurodegenerative disorder affecting, in part, dopaminergic motor neurons of the ventral midbrain and their terminal projections that course to the striatum. Symptomatic strategies focused on dopamine replacement have proven effective at remediating some motor symptoms during the course of disease but ultimately fail to deliver long-term disease modification and lose effectiveness due to the emergence of side effects. Several strategies have been experimentally tested as alternatives for Parkinson's disease, including direct cell replacement and gene transfer through viral vectors. Cellular transplantation of dopamine-secreting cells was hypothesized as a substitute for pharmacotherapy to directly provide dopamine, whereas gene therapy has primarily focused on restoration of dopamine synthesis or neuroprotection and restoration of spared host dopaminergic circuitry through trophic factors as a means to enhance sustained controlled dopamine transmission. This seems now to have been verified in numerous studies in rodents and nonhuman primates, which have shown that grafts of fetal dopamine neurons or gene transfer through viral vector delivery can lead to improvements in biochemical and behavioral indices of dopamine deficiency. However, in clinical studies, the improvements in parkinsonism have been rather modest and variable and have been plagued by graft-induced dyskinesias. New developments in stem-cell transplantation and induced patient-derived cells have opened the doors for the advancement of cell-based therapeutics. In addition, viral-vector-derived therapies have been developed preclinically with excellent safety and efficacy profiles, showing promise in clinical trials thus far. Further progress and optimization of these therapies will be necessary to ensure safety and efficacy before widespread clinical use is deemed appropriate.

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Cell-based therapies in Parkinson’s disease

Cited by 15 publications

References 48 publications

Mesenchymal stem cells for the treatment of neurodegenerative disease

Mesenchymal stem cells for the treatment of neurodegenerative disease

Brain Regeneration in Physiology and Pathology: The Immune Signature Driving Therapeutic Plasticity of Neural Stem Cells

Cell Transplantation and Gene Therapy in Parkinson's Disease

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