Methods comprising apoptosis inhibitors for the generation of transgenic pigs

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Stem Cell Related Patent Number US6680198

Title:Engraftable human neural stem cells
Inventors:Snyder, Evan Y.; Jamaica Plain, MA, USA
Wolfe, John H.; Philadelphia, PA, USA
Kim, Seung U.; Vancouver, Canada
Summary:Described herein is a new primordial human neural stem cell clone comprising both EGF and bFGF receptors, which is maintained as a stable and identifiable cell line in vitro and which is suitable for implantation in vivo into a living host subject. The primordial human neural stem cell clone is described as comprising a pluripotent and self-renewing neural stem cell of human origin, derived from neural stem cells have been isolated from the human fetal telencephalon. Further disclosed are methods by which these self-renewing clones may be genetically engineered prior to transplantation, thereby expressing foreign transgenes in vivo in disseminated locations. Claims of the invention include secretory products which can cross-correct a prototypical genetic metabolic defect in abnormal neurons and glia in vitro as effectively as do murine neural stem cells. Methods of epigenetic propagation and genetic transduction are provided, as are methods of cyropreservation and transplantaion. Therapeutic applications are included, such as in neural cell replacement or in the treatment of extensive inherited metabolic and other neurogenetic human diseases such as Tay-sachs disease.
Abstract:Stable clones of neural stem cells (NSCs) have been isolated from the human fetal telencephalon. In vitro, these self-renewing clones (affirmed by retroviral insertion site) can spontaneously give rise to all 3 fundamental neural cell types (neurons, oligodendrocytes, astrocytes). Following transplantation into germinal zones of the developing newborn mouse brain, they, like their rodent counterparts, can participate in aspects of normal development, including migration along well-established migratory pathways to disseminated CNS regions, differentiation into multiple developmentally- and regionally-appropriate cell types in response to microenvironmental cues, and non-disruptive, non-tumorigenic interspersion with host progenitors and their progeny. Readily genetically engineered prior to transplantation, human NSCs are capable of expressing foreign transgenes in vivo in these disseminated locations. Further supporting their potential for gene therapeutic applications, the secretory products from these NSCs can cross-correct a prototypical genetic metabolic defect in abnormal neurons and glia in vitro as effectively as do murine NSCs. Finally, human cells appear capable of replacing specific deficient neuronal populations in a mouse model of neurodegeneration and impaired development, much as murine NSCs could. Human NSCs may be propagated by a variety of means--both epigenetic (e.g., chronic mitogen exposure) and genetic (transduction of the propagating gene vmyc)--that are comparably safe (vmyc is constitutively downregulated by normal developmental mechanisms and environmental cues) and effective in yielding engraftable, migratory clones, suggesting that investigators may choose the propagation technique that best serves the demands of a particular research or clinical problem. All clones can be cryopreserved and transplanted into multiple hosts in multiple settings.
US Patent Website:Click Here for Full Text of Patent
Title Number:US6680198
Application Number:US1999000398299
Date Filed:20/09/1999
Date Published:20/01/2004
Assignee:The Children's Medical Center Corporation, Boston, MA, USA University of British Columbia, Vancouver, United Kingdom University of Pennsylvania, Philadelphia, PA, USA


 
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