Long-term Evaluation of Bilateral Fetal Nigral Transplantation in Parkinson Disease

Hauser, Robert A.; Freeman, Thomas B.; Snow, Barry; Nauert, M; Gauger, Lisa; Kordower, Jeffrey H.; Olanow, C. Warren

doi:10.1001/archneur.56.2.179

Cited by 335 publications

(196 citation statements)

References 72 publications

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“…Thus, these data suggest that supplementing intrastriatal fetal VM grafts with in vivo injections of viral vector delivering the GDNF gene may decrease the number of VM grafts necessary to re-supply the host striatum with adequate levels of DA. This would be a significant achievement, as the use of eight donors for one human host (Hauser et al, 1999;Olanow et al, 2003) is an obstacle to neural grafting as a treatment option for Parkinson's disease.…”

Section: Discussionmentioning

confidence: 99%

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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Neural transplantation offers the potential of treating Parkinson's disease by grafting fetal dopamine neurons to depleted regions of the brain. However, clinical studies of neural grafting in Parkinson's disease have produced only modest improvements. One of the main reasons for this is the low survival rate of transplanted neurons. The inadequate supply of critical neurotrophic factors in the adult brain is likely to be a major cause of early cell death and restricted outgrowth of fetal grafts placed into the mature striatum. Glial derived neurotrophic factor (GDNF) is a potent neurotrophic factor that is crucial to the survival, outgrowth and maintenance of dopamine neurons, and so is a candidate for protecting grafted fetal dopamine neurons in the adult brain. We found that implantation of adenoassociated virus type 2 encoding GDNF (AAV2-GDNF) in the normal monkey caudate nucleus induced over-expression of GDNF that persisted for at least 6 months after injection. In a 6-month within-animal controlled study, AAV2-GDNF enhanced the survival of fetal dopamine neurons by 4-fold, and increased the outgrowth of grafted fetal dopamine neurons by almost 3-fold in the caudate nucleus of MPTP-treated monkeys, compared with control grafts in the other caudate nucleus. Thus, the addition of GDNF gene therapy to neural transplantation may be a useful strategy to improve treatment for Parkinson's disease.

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Section: Discussionmentioning

confidence: 99%

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Elsworth

Redmond

Léránth

et al. 2008

Experimental Neurology

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“…63 Clinically successful transplantation of fetal tissue with corroborative serial 18 F-dopa PET findings has also been reported for five PD patients in a 2-year open follow-up French study 64 and for six PD patients in a 2-year follow-up series from Tampa, Florida. 65 In the French study grafted putamen Ki values correlated with percentage time "on" during the day and finger dexterity while in an "off" state. Two of the transplanted PD patients in the Florida series died from unrelated causes and at postmortem viable tyrosine hydroxylase staining graft tissue, forming connections with host neurons, was found.…”

Section: Human Fetal Cell Implantation Trialsmentioning

confidence: 95%

Neuroimaging in Parkinson’s disease

Brooks

2004

Neurotherapeutics

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Summary:In this review, the potential role of positron emission tomography and single photon emission computed tomography as biological markers for diagnosing and following the progression of Parkinson's disease (PD) is discussed. Their value for assessing the efficacy of putative neuroprotective agents in PD and for revealing the pharmacological changes underlying the symptomatology and complications of this disorder is also considered. It is concluded that in the future functional imaging will provide a valuable adjunct to clinical assessment when judging the efficacy of putative neuroprotective approaches to PD.

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“…Neither in the open-label nor in the sham-surgery controlled clinical trials, improvements after intrastriatal transplantation of fetal mesencephalic DA-rich tissue in PD patients [4,6,8,9,13,14] have exceeded those found with DBS in the subthalamic nucleus [80]. Moreover, there is no Fig.…”

Section: Toward An Effective and Safe Cell Therapy For Pdmentioning

confidence: 97%

“…Dopaminergic Grafts Can Survive and Become Morphologically Integrated in the PD Patient's Brain Following implantation of postmitotic DA neuroblasts from the ventral mesencephalon of 6-to 9-weekold human fetuses, positron emission tomography (PET) detected increases in 6-L-[ 18 F]-fluorodopa ( 18 F-dopa) uptake ( Fig. 1) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], and histopathological studies have shown long-term, extensive synaptic reinnervation in the striatum [13,[20][21][22][23][24][25][26][27].…”

Section: Can Da Neurons Be Replaced and Neural Grafts Have Functionalmentioning

confidence: 99%

Cell Therapeutics in Parkinson's Disease

Lindvall

Björklund

2011

Neurotherapeutics

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The main pathology underlying motor symptoms in Parkinson's disease (PD) is a rather selective degeneration of nigrostriatal dopamine (DA) neurons. Intrastriatal transplantation of immature DA neurons, which replace those neurons that have died, leads to functional restoration in animal models of PD. Here we describe how far the clinical translation of the DA neuron replacement strategy has advanced. We briefly summarize the lessons learned from the early clinical trials with grafts of human fetal mesencephalic tissue, and discuss recent findings suggesting susceptibility of these grafts to the disease process longterm after implantation. Mechanisms underlying graftinduced dyskinesias, which constitute the only significant adverse event observed after neural transplantation, and how they should be prevented and treated are described. We summarize the attempts to generate DA neurons from stem cells of various sources and patient-specific DA neurons from fully differentiated somatic cells, with particular emphasis on the requirements of these cells to be useful in the clinical setting. The rationale for the new clinical trial with transplantation of fetal mesencephalic tissue is described. Finally, we discuss the scientific and clinical advancements that will be necessary to develop a competitive cell therapy for PD patients.

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Long-term Evaluation of Bilateral Fetal Nigral Transplantation in Parkinson Disease

Cited by 335 publications

References 72 publications

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

AAV2-mediated gene transfer of GDNF to the striatum of MPTP monkeys enhances the survival and outgrowth of co-implanted fetal dopamine neurons

Neuroimaging in Parkinson’s disease

Cell Therapeutics in Parkinson's Disease

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