Methods comprising apoptosis inhibitors for the generation of transgenic pigs

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Stem Cell Related Patent Number US6528306

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:This invention introduces a novel clone of genetically modified human neural stem cells (hNSCs) stably maintained in vitro. Described herein is an individually distinct cell line having multiple primordial hNSCs isolated from the human fetal telencephalon. Such self-renewing clones are described as spontaneously giving rise to all 3 fundamental neural cell types, namely, neurons, oligodendrocytes, and astrocytes such that they can participate in aspects of normal development following transplantation into the germinal zones of a developing newborn mouse brain, 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. Further disclosed are methods of genetically engineering the hNSCs prior to transplantation so that they express foreign transgenes in vivo in disseminated locations. Claims of the invention include the use of secretory products from these hNSCs for the cross-correction of a prototypical genetic metabolic defect in abnormal neurons and glia in vitro with the same efficacy as murine NSCs. Further disclosed are methods of transduction and exposure in both the epigenetic and genetic propagation of such hNSCs. Therapeutic applications are included, such as in the treatment of neurogenetic disorders including Tay-Sachs disease. This invention represents a continuation of other applications filed by the same assignee and inventors.
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:US6528306
Application Number:US1999000398298
Date Filed:20/09/1999
Date Published:04/03/2003
Assignee:The Children's Medical Center Corporation, Boston, MA, USA The University of British Columbia Canada The University of Pennsylvania, Philadelphia, PA, USA


 
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