Bilateral fetal nigral transplantation into the postcommisural putamen in Parkinson's disease

Department of Surgery, University of South Florida, Tampa, USA.
Annals of Neurology (Impact Factor: 9.98). 09/1995; 38(3):379-88. DOI: 10.1002/ana.410380307
Source: PubMed

ABSTRACT We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the "off" state, Schwab-England disability score during the "off" state, percent "off" time, and percent "on" time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.

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Available from: Cesar V Borlongan, Sep 29, 2015
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    • "The experimental approach of cell transplantation is one in which the glial response has been more specifically addressed. Two distinct types of cell transplantation have been tested in the clinic—cell suspensions, prepared by mechanically dissociating the cells prior to implantation (Lindvall et al., 1990; Mendez et al., 2002; Freeman and Brundin, 2006) and solid grafts, where donor tissue is transplanted as small pieces (Freeman et al., 1995, 2000; Kordower et al., 1997; Olanow et al., 2003; Freeman and Brundin, 2006; Cicchetti et al., 2009). Each of these strategies is associated with a different pattern and intensity of gliosis. "
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    ABSTRACT: The role of glial cells in the pathogenesis of many neurodegenerative conditions of the central nervous system (CNS) is now well established (as is discussed in other reviews in this special issue of Frontiers in Neuropharmacology). What is less clear is whether there are changes in these same cells in terms of their behavior and function in response to invasive experimental therapeutic interventions for these diseases. This has, and will continue to become more of an issue as we enter a new era of novel treatments which require the agent to be directly placed/infused into the CNS such as deep brain stimulation (DBS), cell transplants, gene therapies and growth factor infusions. To date, all of these treatments have produced variable outcomes and the reasons for this have been widely debated but the host astrocytic and/or microglial response induced by such invasively delivered agents has not been discussed in any detail. In this review, we have attempted to summarize the limited published data on this, in particular we discuss the small number of human post-mortem studies reported in this field. By so doing, we hope to provide a better description and understanding of the extent and nature of both the astrocytic and microglial response, which in turn could lead to modifications in the way these therapeutic interventions are delivered.
    Frontiers in Pharmacology 07/2014; 5:139. DOI:10.3389/fphar.2014.00139 · 3.80 Impact Factor
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    • "Positron emission tomography has also been valuable in monitoring the results of neuronal transplantation trials. While both F-DOPA uptake (Freeman et al, 1995; Kordower et al, 1995; Ma et al, 2010; Figure 2 Positron emission tomography (PET) images depicting cerebral blood flow (CBF), oxygen extraction ratio (OER), and cerebral metabolic rate of oxygen (CMRO 2 ) of a patient after a left hemisphere transient ischemic attack (1ST), 7 hours after a major stroke (2ND), and 4 days after the stroke (3RD). The high oxygen extraction ratio seen within hours after the stroke fell in association with a decline in cortical oxygen metabolism (Wise et al, 1983). "
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    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2012; 32(7):1426-54. DOI:10.1038/jcbfm.2012.20 · 5.41 Impact Factor
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    • "Recent studies also suggest that the engraftment of stem cells or progenitors can up-regulate or enhance existing endogenous progenitor populations [12] [13] [14]. Studies have employed neural cell grafts obtained from the fetal ventral mesencephalic (VM) dopaminergic neurons [15] [16] [17] [18] [19] [20]. However, this frequently resulted in significant dyskinesia [21] [22] [23] [24]. "
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    ABSTRACT: Human adult olfactory epithelium contains neural progenitors (hONPs) which replace damaged cellular components throughout life. Methods to isolate and expand the hONPs which form neurospheres in vitro have been developed in our laboratory. In response to morphogens, the hONPs differentiate along several neural lineages. This study optimized conditions for the differentiation of hONPs towards dopaminergic neurons. The hONPs were treated with Sonic hedgehog (Shh), in the presence or absence of retinoic acid (RA) and/or forskolin (FN). Transcription factors (nurr1, pitx3 and lmx1a) that promote embryonic mouse or chicken dopaminergic development were employed to determine if they would modulate lineage restriction of these adult human progenitors. Four expression vectors (pIRES-pitx3-nurr1, pLN-CX2-pitx3, pLNCX2-nurr1 and pLNCX2-lmx1a) were transfected into the hONPs, respectively. Transcription factor expression and the rate-limiting enzyme in dopamine synthesis tyrosine hydroxylase (TH) were detected in the transfected cells after 4 month-selection with G418, indicating transfected hONPs were stably restricted towards a dopaminergic lineage. Furthermore, a dopamine enzyme immunoassay (EIA) was employed to detect the synthesis and release of dopamine. The most efficient transfection paradigm was determined. Several neurotrophic factors were detected in the pre-transfected hONPs which have potential roles in the maintenance, survival and proliferation of dopaminergic neurons. Therefore the effect of transfection on the neurotrophin synthesis was examined. Transfection did not alter synthesis. The use of olfactory progenitors as a cell-based therapy for Parkinson’s disease (PD) would allow harvest without invasive surgery, provide an autologous cell population, eliminate need for immunosuppression and avoid the ethical concerns associated with embryonic tissues. This study suggests that specific transcription factors and treatment with morphogens can restrict human adult olfactory-derived progenitors to a dopaminergic neuronal lineage. Future studies will evaluate the utility of these unique cells in cell-replacement paradigms for the treatment of PD like animal models.
    Stem Cell Discovery 10/2011; 1(3):29-43. DOI:10.4236/scd.2011.13004
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