Clonal Human (hNT) Neuron Grafts for Stroke Therapy

Nelson, Peter T.; Kondziolka, Douglas; Wechsler, Lawrence R.; Goldstein, Steven; Gebel, James; DeCesare, Sharon; Elder, Elaine M.; Zhang, Paul J.; Jacobs, Alan J.; McGrogan, Michael; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1016/s0002-9440(10)62546-1

Cited by 214 publications

(43 citation statements)

References 30 publications

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“…A post mortem neuropathological examination showed no signs of inflammation, tumor formation or infection at the graft site. Because NT-2 neurons are polyploid for chromosome 21 but not 13, grafted neurons could be unambiguously identified in the human brain tissue with a cocktail of specific fluorescent in situ hybridization probes at the neural implantation site [149]. Consistent with previous animal studies, these results confirm that grafted NT-2 neurons do not revert to a neoplasm and further show that a population of implanted neuron can survive for longer than 2 years in the brain of a human patient.…”

Section: Cerebral Ischemiasupporting

confidence: 85%

“…This finding may reflect therapeutic success of the grafting. Transplantation studies also propose that NT-2 neurons are safe for engraftment in human stroke patients [148][149][150][151], but whether they induce symptomatic relief from functional motor deficits still remains doubtful. Taken together, the transplantation studies suggest that a functional integration of NT-2 neurons into the adult CNS is likely.…”

Section: Cerebral Ischemiamentioning

confidence: 99%

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Human Model Neurons in Studies of Brain Cell Damage and Neural Repair

Paquet-Durand¹,

Bicker

2007

CMM

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Disorders of the central nervous system are a major concern in modern human societies. Studies of these disorders require the use of suitable model systems that accurately reproduce the human situation. In this article we focus on the possibilities of using the human NT-2 teratocarcinoma cell line for studies on neuronal differentiation, cellular function and neurodegeneration. Neurons generated from undifferentiated NT-2 precursor cells show neuronal morphology, express neuronal markers, exhibit action potentials and have the advantage of homogeneous cellular composition of clonally derived cells. They release a number of different neurotransmitters, respond to stimulation with glutamate, gamma-amino-butyric acid, and nitric oxide, and form functional synapses in culture. Depending on the differentiation protocol, NT-2 cells also have the capacity to develop into glial cells. Different neuronal differentiation procedures and biological properties of NT-2 neurons are described in the text. In transplantation experiments, differentiated NT-2 neurons integrated successfully into the nervous systems of both experimental animals and human patients without evidence for tumor formation, underlining their value for both basic research and clinical applications. We discuss some potential applications in the fields of basic research, drug discovery, and therapy of CNS damage with particular emphasis on neuronal transplantation and different cell death mechanisms in neuronal degeneration. Grafting of NT-2 neurons has been shown to effectively reverse functional defects in animal disease models. Moreover, an ongoing phase 2 randomized clinical trial indicates the safety and feasibility of NT-2 neuron transplantation for the treatment of human patients with cerebral stroke.

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Section: Cerebral Ischemiasupporting

confidence: 85%

Section: Cerebral Ischemiamentioning

confidence: 99%

Human Model Neurons in Studies of Brain Cell Damage and Neural Repair

Paquet-Durand¹,

Bicker

2007

CMM

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“…Encouraging clinical data, with some transplanted stroke patients already at 4 years posttransplantation (36,38), Starting on the day of surgery (following recovery from anesthesia) and daily up to 3 days postsurgery, animals suggest that intracerebral transplantation therapy is feasible for stroke.…”

Section: Introductionmentioning

confidence: 99%

Melatonin-Secreting Pineal Gland: A Novel Tissue Source for Neural Transplantation Therapy in Stroke

Sumaya

Moss

et al. 2003

Cell Transplant

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Chronic systemic melatonin treatment attenuates abnormalities produced by occlusion of middle cerebral artery (MCA) in adult rats. Because the pineal gland secretes high levels of melatonin, we examined in the present study whether transplantation of pineal gland exerted similar protective effects in MCA-occluded adult rats. Animals underwent same-day MCA occlusion and either intrastriatal transplantation of pineal gland (harvested from 2-month-old rats) or vehicle infusion. Behavioral tests (from day of surgery to 3 days posttransplantation) revealed that transplanted stroke rats displayed significantly less motor asymmetrical behaviors than vehicle-infused stroke rats. Histological analysis at 3 days posttransplantation revealed that transplanted stroke rats had significantly smaller cerebral infarction than vehicle-infused rats. Additional experiments showed that pinealectomy affected transplantation outcome, in that transplantation of pineal gland only protected against stroke-induced deficits in stroke animals with intact pineal gland, but not in pinealectomized stroke rats. Interestingly, nonpinealectomized vehicle-infused stroke rats, as well as pinealectomized transplanted stroke rats, had significantly lower melatonin levels in the cerebrospinal fluid than nonpinealectomized transplanted stroke rats. We conclude that intracerebral transplantation of pineal gland, in the presence of host intact pineal gland, protected against stroke, possibly through secretion of melatonin.

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“…0.006, respectively), suggesting an effect from the transplanted cells [22] . The long-term viability and safety of these transplanted cells is suggested by a post-mortem examination of the brain of a patient without any detectable clinical improvement who died of an unrelated cause 2 years after surgery, revealing neuronspecifi c phenotypes within the implanted region without neoplastic changes [23] .…”

Section: Trials In Humansmentioning

confidence: 99%

Cell Transplantation for Ischemic Stroke

Vora

Jovin²,

Kondziolka³

2006

Neurodegener Dis

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Cell replacement therapy has been evaluated as a regenerative strategy for patients with fixed neurologic deficits after ischemic stroke. Animal models have identified specific cell lines which lead to regeneration and improvement in behavior and motor function after implantation into areas of ischemic injury. This has led to the development of pilot studies in humans, which have mainly investigated the safety and pilot efficacy of such approaches with promising early results. As research in this area progresses, further prospective trials are necessary not only to demonstrate clinical efficacy but also to understand the mechanisms underlying the early positive experiences, to select appropriate patients for cell replacement therapy, and to elucidate the optimal timing and mode of cell delivery.

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Clonal Human (hNT) Neuron Grafts for Stroke Therapy

Cited by 214 publications

References 30 publications

Human Model Neurons in Studies of Brain Cell Damage and Neural Repair

Human Model Neurons in Studies of Brain Cell Damage and Neural Repair

Melatonin-Secreting Pineal Gland: A Novel Tissue Source for Neural Transplantation Therapy in Stroke

Cell Transplantation for Ischemic Stroke

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