Parkinson's Disease and Stem Cell Therapy
Parkinson's disease is also called Parkinson's, idiopathic parkinsonism, primary parkinsonism, PD, or paralysis agitans is a degenerative disorder of the central nervous system.
Common degeneration results from the death of dopamine containing cells in the area of the midbrain.
The cause of cell-death is currently unknown. In the early stages of the disease, the most obvious symptoms are movement-related which includes shaking, rigidity, slowness of movement and trouble walking.
Later stage symptoms include cognitive and behavioural problems with dementia commonly occurring in the advanced stages. Other symptoms include sensory, sleep and emotional problems.
PD is more common in the elderly with most cases occurring after the age of 50.
STEM CELL RESEARCH
Parkinson's stem cell research shows promise
Tue, 08 Nov 2011 13:33:00 EST
New stem cell research may point to ways to replace the brain cells that die off in Parkinson’s disease, The Guardian has today reported.
In the research, scientists were able to use human stem cells to create dopamine neurons, which had similar properties to the types of brain cells lost in Parkinson’s disease. When the scientists introduced the new cells into the brains of mice, rats and monkeys with Parkinson’s-like lesions, the animals were able to survive, and in the mice and rats the movement problems normally seen were reversed. In addition, no cancer or uncontrolled cell growth was seen after the cells had been introduced, two safety concerns associated with stem cell therapy.
The results of this study are extremely promising, although more work is required before stem cell-based therapy can be used to treat Parkinson’s disease in humans. That said, the neurons which the researchers have created could have immediate applications in research, such as being used in cell-based models of Parkinson’s disease. This in turn could help find a cure for Parkinson’s disease, such as developing new drugs faster.
Where did the story come from?
The study was carried out by researchers from the Memorial Sloan-Kettering Cancer Centre, New York and several other American research institutions. It was funded by the US National Institutes of Health, the US National Institute of Neurological Disorders and Stroke, the European Commission NeuroStemcell project and several other research funds. The study was published in the peer-reviewed journal, Nature.
This story was covered by The Guardian, which accurately presented the research and included passages and images making it clear that the research was performed in animals. The newspaper also included quotes from Parkinson’s UK and seemed to allow the reader to conclude that stem cell therapy is still some way off, but that this finding is promising for the future.
What kind of research was this?
This was a laboratory-based and animal study. The authors aimed to develop a method that would allow them to create human dopamine neurons (types of brain cells that die in Parkinson’s disease) from human stem cells. They then wanted to test whether these neurons could be used to reverse the signs and symptoms of Parkinson’s disease in animal models.
These sorts of questions can only be answered by laboratory and animal based studies. Only once the technique has been thoroughly tested and evaluated through a significant amount animal research can it be considered for use in small, experimental human trials.
What did the research involve?
The researchers used recent research on dopamine neurons to develop a new a new laboratory-based protocol to create them from stem cells. They then tested the features of the cells that they created to see whether they were similar to the dopamine neurons found within the midbrain (the part of the brain where Parkinson’s disease occurs).
The researchers then wanted to test whether the dopamine neurons they created could survive if introduced into the brains of animals. They also wanted to check that there was no risk of “neural overgrowth” (i.e. a potentially harmful overproduction of new brain cells), and that the cells they introduced did not form the incorrect cell type. The researchers then determined whether the cells they had created in the laboratory could repair the damage seen in animals with Parkinson’s-type lesions. The animal models had been created by treating the animals with specific chemicals, as Parkinson’s disease is not known to occur in any species other than humans.
What were the basic results?
The researchers managed to develop a method that would allow them to create dopamine neurons which were very similar to the dopamine neurons normally found in the midbrain. They found that these neurons could survive when injected into the brains of healthy mice, and did not overgrow (where they continue to grow abnormally) after injection. The dopamine neurons also successfully grafted in the brains of mice and rats treated with chemicals to create models of Parkinson’s disease.
These introduced neurons reversed the movement problems seen in these animals. Finally, as the number of dopamine neurons required in a mouse or rat is much lower than the number needed in a human, the researchers investigated whether the technique could be scaled up to treat two monkeys with Parkinson’s-like lesions. Again, the neurons successfully grafted into the brains of two monkeys.
How did the researchers interpret the results?
The researchers conclude that the “excellent dopamine neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson’s disease.”
In this study, researchers managed to create dopamine neurons from human stem cells. These neurons were very similar to the neurons found in the midbrain, and therefore were very similar to the neurons lost in Parkinson’s disease. The cells they created were able to survive when introduced into the brains of mice, rats and monkeys with Parkinson’s-like lesions, and reversed the movement problems seen in mice and rats. No problems with neural overgrowth were seen.
The results of this study are extremely promising, but much more work is required before stem cell-based therapy can be used to treat Parkinson’s disease in humans. For example, although the animals regained movement, the complexity of the human brain is greater than that seen in the animals tested. It would need to be determined whether the use of stem cells in this way might negatively affect higher functions such as speech or complex memory.
Also, there other points to consider, such as how closely the chemically induced brain changes the animals underwent represented Parkinson’s disease, and whether the use of stem cells in this way would be safe or effective in the long-term.
However, the neurons that the researchers have created could also have useful and important applications for research in this area. In particular, cell-based models of Parkinson’s disease could now be created and used for tasks such as developing new drugs faster.
The Guardian notes that doctors have already tried transplanting foetal brain tissue into Parkinson's patients in the 1990s with inconsistent or unpleasant results: some patients got better while others experienced runaway involuntary movements. In these cases, the timing of the transplant seemed to be important and it is possible that this new technique, which did not produce “cellular overgrowth”, will in time lead to further transplants that are safer.
Kriks S, Shim J, Piao J et al. Nature, November 6 2011
Stem cell-based therapies in Parkinson's disease: future hope or current treatment option?
Loewenbrück K, Storch A.
Source Department of Neurology, Dresden University of Technology, Fetscherstrasse 74, 01307 Dresden, Germany.
Parkinson's disease (PD) is one of the most frequent neurodegenerative diseases and represents a major therapeutic challenge because of the so far missing therapeutic means to influence the ongoing loss of dopaminergic innervation to the striatum.
Cell replacement has raised hope to offer the first restorative treatment option. Clinical trials have provided "proof of principle" that transplantation of dopamine-producing neurons into the striatum of PD patients can achieve symptomatic relief given that the striatum is sufficiently re-innervated.
Various cell sources have been tested, including fetal ventral midbrain tissue, embryonic stem cells, fetal and adult neural stem cells and, after a ground-breaking discovery, induced pluripotent stem cells. Although embryonic and induced pluripotent stem cells have emerged as the most promising candidates to overcome most of the obstacles to clinical successful cell replacement, each cell source has its unique drawbacks. This review does not only provide a comprehensive overview of the different cellular candidates, including their assets and drawbacks, but also of the various additional issues that need to be addressed in order to convert cellular replacement therapies from an experimental to a clinically relevant therapeutic alternative.
PMID: 21437664 [PubMed - in process]
Cell transplantation and gene therapy in Parkinson's disease.
2011 Jan-Feb;78(1):126-58. doi: 10.1002/msj.20233.
Wakeman DR, Dodiya HB, Kordower JH.
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.
© 2011 Mount Sinai School of Medicine.
PMID: 21259269 [PubMed - indexed for MEDLINE]
Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease.
J Clin Invest. 2011 May 16;
Authors: Rhee YH, Ko JY, Chang MY, Yi SH, Kim D, Kim CH, Shim JW, Jo AY, Kim BW, Lee H, Lee SH, Suh W, Park CH, Koh HC, Lee YS, Lanza R, Kim KS, Lee SH
Parkinson disease (PD) involves the selective loss of midbrain dopamine (mDA) neurons and is a possible target disease for stem cell-based therapy. Human induced pluripotent stem cells (hiPSCs) are a potentially unlimited source of patient-specific cells for transplantation. However, it is critical to evaluate the safety of hiPSCs generated by different reprogramming methods.
Here, we compared multiple hiPSC lines derived by virus- and protein-based reprogramming to human ES cells (hESCs). Neuronal precursor cells (NPCs) and dopamine (DA) neurons delivered from lentivirus-based hiPSCs exhibited residual expression of exogenous reprogramming genes, but those cells derived from retrovirus- and protein-based hiPSCs did not.
Furthermore, NPCs derived from virus-based hiPSCs exhibited early senescence and apoptotic cell death during passaging, which was preceded by abrupt induction of p53.
In contrast, NPCs derived from hESCs and protein-based hiPSCs were highly expandable without senescence. DA neurons derived from protein-based hiPSCs exhibited gene expression, physiological, and electrophysiological properties similar to those of mDA neurons. Transplantation of these cells into rats with striatal lesions, a model of PD, significantly rescued motor deficits. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of PD.
Related Articles Advances in Neurotrophic Factor and Cell-Based Therapies for Parkinson's Disease: A Mini-Review. Gerontology. 2016;62(3):371-80 Authors: Staudt MD, Di Sebastiano AR, Xu H, Jog M, Schmid S, Foster P, Hebb MO Abstract Parkinson's disease (PD) affects an estimated 7-10 million people worldwide and remains without definitive or disease-modifying treatment. There have been many recent developments in cell-based therapy (CBT) to replace lost circuitry and provide chronic biological sources of therapeutic agents to the PD-affected brain. Early neural transplantation studies underscored the challenges of immune compatibility, graft integration and the need for renewable, autologous graft sources. Neurotrophic factors (NTFs) offer a potential class of cytoprotective pharmacotherapeutics that may complement dopamine (DA) replacement and CBT strategies in PD. Chronic NTF delivery may be an integral goal of CBT, with grafts consisting of autologous drug-producing (e.g., DA, NTF) cells that are capable of integration and function in the host brain. In this mini-review, we outline the past experience and recent advances in NTF technology and CBT as promising and integrated approaches for the treatment of PD. PMID: 26330171 [PubMed - indexed for MEDLINE]Read more...
Estradiol Facilitates Functional Integration of iPSC-Derived Dopaminergic Neurons into Striatal Neuronal Circuits via Activation of Integrin α5β1.
Related Articles Estradiol Facilitates Functional Integration of iPSC-Derived Dopaminergic Neurons into Striatal Neuronal Circuits via Activation of Integrin α5β1. Stem Cell Reports. 2016 Apr 12;6(4):511-24 Authors: Nishimura K, Doi D, Samata B, Murayama S, Tahara T, Onoe H, Takahashi J Abstract For cell transplantation therapy for Parkinson's disease (PD) to be realized, the grafted neurons should be integrated into the host neuronal circuit to restore the lost neuronal function. Here, using wheat-germ agglutinin-based transsynaptic tracing, we show that integrin α5 is selectively expressed in striatal neurons that are innervated by midbrain dopaminergic (DA) neurons. In addition, we found that integrin α5β1 was activated by the administration of estradiol-2-benzoate (E2B) in striatal neurons of adult female rats. Importantly, we observed that the systemic administration of E2B into hemi-parkinsonian rat models facilitates the functional integration of grafted DA neurons derived from human induced pluripotent stem cells into the host striatal neuronal circuit via the activation of integrin α5β1. Finally, methamphetamine-induced abnormal rotation was recovered earlier in E2B-administered rats than in rats that received other regimens. Our results suggest that the simultaneous administration of E2B with stem cell-derived DA progenitors can enhance the efficacy of cell transplantation therapy for PD. PMID: 26997644 [PubMed - indexed for MEDLINE]Read more...