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Novel approaches for long-term gene ...

Sclimenti, Christopher Ryan.

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Novel approaches for long-term gene therapy.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Novel approaches for long-term gene therapy./
Author:	Sclimenti, Christopher Ryan.
Description:	239 p.
Notes:	Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1071.
Contained By:	Dissertation Abstracts International64-03B.
Subject:	Biology, Genetics. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3085367

Novel approaches for long-term gene therapy.
Sclimenti, Christopher Ryan.

Novel approaches for long-term gene therapy. - 239 p.

Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1071.

Thesis (Ph.D.)--Stanford University, 2003.

The unique features associated with Epstein-Barr virus (EBV) vectors have led to several advancements in biotechnology such as novel systems for regulated gene expression and gene therapy. My colleagues and I have demonstrated that vectors incorporating components from EBV for retention and from human genomic DNA for replication greatly enhance the level and duration of marker gene expression in dividing cultured cells. The same types of vectors were tested in vivo by high pressure tail vein injection of naked DNA in mice, resulting in liver delivery and expression. The therapeutic gene was a human factor IX (hFIX) mini-gene comprising genomically-derived 5 ', 3', and intronic sequences that provided relatively good gene expression in vivo. We demonstrated that addition of the EBV EBNA1 gene and its family of repeats binding sites provided a 10--100-fold increase in prolonged hFIX expression in mouse liver. A single 25 mug dose of vector DNA generated normal (>5 mug/ml) levels of hFIX throughout the 8 month duration of the experiment. The EBV sequences also significantly enhanced stable expression of a vector carrying the full genomic hFIX gene delivered to mouse liver. These results underline the crucial importance of appropriate gene expression signals on gene therapy vectors and the utility of EBV sequences in particular for increasing stable gene expression.Subjects--Topical Terms:

1017730
Biology, Genetics.

Novel approaches for long-term gene therapy.
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100 1 $a Sclimenti, Christopher Ryan. $3 1949178
245 1 0 $a Novel approaches for long-term gene therapy.
300 $a 239 p.
500 $a Source: Dissertation Abstracts International, Volume: 64-03, Section: B, page: 1071.
500 $a Adviser: Michele P. Calos.
502 $a Thesis (Ph.D.)--Stanford University, 2003.
520 $a The unique features associated with Epstein-Barr virus (EBV) vectors have led to several advancements in biotechnology such as novel systems for regulated gene expression and gene therapy. My colleagues and I have demonstrated that vectors incorporating components from EBV for retention and from human genomic DNA for replication greatly enhance the level and duration of marker gene expression in dividing cultured cells. The same types of vectors were tested in vivo by high pressure tail vein injection of naked DNA in mice, resulting in liver delivery and expression. The therapeutic gene was a human factor IX (hFIX) mini-gene comprising genomically-derived 5 ', 3', and intronic sequences that provided relatively good gene expression in vivo. We demonstrated that addition of the EBV EBNA1 gene and its family of repeats binding sites provided a 10--100-fold increase in prolonged hFIX expression in mouse liver. A single 25 mug dose of vector DNA generated normal (>5 mug/ml) levels of hFIX throughout the 8 month duration of the experiment. The EBV sequences also significantly enhanced stable expression of a vector carrying the full genomic hFIX gene delivered to mouse liver. These results underline the crucial importance of appropriate gene expression signals on gene therapy vectors and the utility of EBV sequences in particular for increasing stable gene expression.
520 $a A better approach to gene therapy may be to use methods that result in permanent genomic modification. This outcome can be achieved by using site-specific recombinases. The enzyme directs integration of plasmids bearing the phage attB recognition site into pseudo attP sites, a set of native sequences related to the phage attP recognition site.{09} After two cycles of DNA shuffling and screening in Escherichia coli, I obtained evolved integrases that possessed significant improvements in integration frequency and sequence specificity at a pseudo attP sequence located on human chromosome 8. These results were obtained in the native genomic environment of living human cells. Such integrases represent custom integration tools that will be useful for modifying the genomes of higher eukaryotic cells.
590 $a School code: 0212.
650 4 $a Biology, Genetics. $3 1017730
690 $a 0369
710 2 0 $a Stanford University. $3 754827
773 0 $t Dissertation Abstracts International $g 64-03B.
790 1 0 $a Calos, Michele P., $e advisor
790 $a 0212
791 $a Ph.D.
792 $a 2003
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3085367