Transfectable and Transplantable Postmitotic Human Neurons: A Potential “Platform” for Gene Therapy of Nervous System Diseases

Trojanowski, John Q.; Kleppner, Sofie R.; Hartley, Rebecca S.; Murata, Masayuki; Fraser, Nigel W.; Kesari, Santosh; Lee, Virginia M.‐Y.

doi:10.1006/exnr.1996.6393

Cited by 90 publications

(67 citation statements)

References 29 publications

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“…Moreover, NT2 neurons provide a rich source of neurons for use in cell transplantation therapy, which has recently been suggested to be one of the most promising treatment strategies for various neurodegnerative diseases (9). Transplantation of neurons into the CNS-lesioned site has resulted in the restoration of the normal nigrostriatal pathway in patients suffering from Parkinson's disease (20). Thus, the rapid protocol described in the present study will be useful in providing an efficient way to produce large quantities of neurons for basic research and for applications in cell therapy.…”

Section: Research Repo R Tsmentioning

confidence: 99%

“…These NT2-N neurons have been used as model systems for the study of neurodegenerative diseases such as Alzheimer's disease (7). The potential applications of NT2-N neurons in cell transplantation therapy for CNS disorders, and their use as vehicles for delivering exogenous proteins into the human brain for gene therapy, were recently demonstrated (20).…”

Section: Introductionmentioning

confidence: 99%

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Production of Human CNS Neurons from Embryonal Carcinoma Cells Using a Cell Aggregation Method

Cheung

Hui

et al. 1999

BioTechniques

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Section: Research Repo R Tsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Production of Human CNS Neurons from Embryonal Carcinoma Cells Using a Cell Aggregation Method

Cheung

Hui

et al. 1999

BioTechniques

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“…When transplanted, these neuronal cells survived, extended processes, expressed neurotransmitters, formed functional synapses, and integrated with the host. 16,33 During the retinoic acid induction process, significant changes were seen in the LBS neuron precursor cells that resulted in the loss of neuroepithelial markers and the appearance of neuronal markers. The final cell product was a Ն 95% pure population of human neuronal cells that appeared virtually indistinguishable from terminally differentiated, postmitotic neurons.…”

Section: The Biology Of Cellular Transplantationmentioning

confidence: 99%

“…Animal transplantation studies of LBS neurons reveal graft survival, a mature neuronal phenotype, and integration into the host brain in vivo. 16,33,34 Layton BioScience neurons xenografted into different regions of the CNS of nude mice showed viable cells in 90% of recipients, with some grafts surviving for up to 14 months. Grafted LBS neurons initially remained similar to their in vitro counterparts, but then progressively acquired the phenotype of fully mature neurons in vivo.…”

Section: Potential Mechanisms Of Cell Transplantationmentioning

confidence: 99%

Stroke repair with cell transplantation: neuronal cells, neuroprogenitor cells, and stem cells

Kondziolka¹,

Wechsler²

2008

FOC

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✓ Stroke is a common cause of death and disability. The role of cellular transplantation to promote functional recovery has been explored. Preclinical studies first established the potential for cultured neuronal cells derived from a teratocarcinoma cell line to be tested for safety and efficacy in the treatment of human stroke. In animal models of stroke that caused reproducible learning and motor deficits, injection of neuronal cells resulted in a return of learning behavior retention time and motor function. In this report the authors review several current concepts for cellular repair, discuss important patient selection and surgical technique issues, and discuss plans for future experiments.

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“…53,54 Therefore, we investigate whether Ad/5HRE-3NRSE can mediate hypoxia-inducible gene expression selectively in differentiated human NT2/Ns. Indeed, following hypoxia, Ad/5HRE-3NRSE infected NT2/Ns cultures showed a 22-fold induction in the reporter luciferase activity after 1% O 2 hypoxia for 6 h. No significant induction of reporter activity occurred in cultured NT2 glial cells (Figure 4a).…”

Section: Hypoxia-inducible Neuron-selective Adenoviral Vectors D Huanmentioning

confidence: 99%

A novel adenoviral vector which mediates hypoxia-inducible gene expression selectively in neurons

2005

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Selective gene expression in neurons is still a challenge. We have developed several expression vectors using a combination of neuron restrictive silencer elements (NRSEs), hypoxia responsive elements (HREs) and CMV minimal promoter (CMVmp). These elements were packaged into replication defective adenovirus to target gene expression selectively in neurons in a hypoxia-regulated manner. Neuronal selectivity and responsiveness to hypoxia of these novel constructs were determined empirically in both neural cell lines and primary cerebellar granule neurons (CGNs). The construct p5HRE-3NRSE exhibited not only the highest level of reporter gene expression in neuronal cells but also in an oxygen concentration-dependent manner when compared with all other constructs. As expected, this construct did not elicit reporter gene expression in non-neuronal cells including human HEK293A and HT29 cells, rat NRK cells, mouse 3T6 cells and 3T3 L1 cells. This construct was packaged into a replication defective adenoviral vector (Ad/5HRE-3NRSE) to determine neuron-selective and hypoxia-inducible gene expression in cultured mouse postmitotic primary CGNs and differentiated human NT2 neurons (NT2/Ns). Remarkably, in response to hypoxia, Ad/5HRE-3NRSE showed strong hypoxia-inducible gene expression selectively in neurons (12-fold induction in CGNs and 22-fold in NT2/Ns), but not in glial cells. Taken together, this vector with restricted gene expression to neurons under the regulation of hypoxia will be a useful tool for investigations of mechanisms of neuronal damage caused by ischemic insult.

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Transfectable and Transplantable Postmitotic Human Neurons: A Potential “Platform” for Gene Therapy of Nervous System Diseases

Cited by 90 publications

References 29 publications

Production of Human CNS Neurons from Embryonal Carcinoma Cells Using a Cell Aggregation Method

Production of Human CNS Neurons from Embryonal Carcinoma Cells Using a Cell Aggregation Method

Stroke repair with cell transplantation: neuronal cells, neuroprogenitor cells, and stem cells

A novel adenoviral vector which mediates hypoxia-inducible gene expression selectively in neurons

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