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Phage integrases for gene therapy: ...

Olivares, Eric Chace.

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Phage integrases for gene therapy: From concept to application.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Phage integrases for gene therapy: From concept to application./
作者:	Olivares, Eric Chace.
面頁冊數:	170 p.
附註:	Source: Dissertation Abstracts International, Volume: 64-05, Section: B, page: 2012.
Contained By:	Dissertation Abstracts International64-05B.
標題:	Biology, Genetics. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3090651

Phage integrases for gene therapy: From concept to application.
Olivares, Eric Chace.

Phage integrases for gene therapy: From concept to application. - 170 p.

Source: Dissertation Abstracts International, Volume: 64-05, Section: B, page: 2012.

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

Long term correction of many genetic disorders requires the gene therapy vector to become integrated into the recipient chromosome. This allows for reliable transmission of the introduced genes as the cell divides throughout the lifetime of the patient. Current solutions take advantage of the natural machinery of viruses to integrate the therapeutic gene into the recipient chromosome. While this strategy has proven effective in many cases, the use of viruses on human patients poses serious safety concerns. The integrating viruses most commonly used for gene therapy (retroviruses and lentiviruses) insert their genomes into the chromosome in a random fashion, without regard for the importance of the target site. This type of insertion has the potential of causing deleterious mutations, and has recently been documented as the cause of two leukemias in a gene therapy clinical trial. Here, I document the development of a novel system utilizing prokaryotic phage integrases that allows for site-specific integration of the gene therapy vector into safe places in patient genome. In nature, bacteriophage integrases catalyze the integration of the prophage genome into the chromosome of the host bacterium. Their function is distinct from that of retroviral integrases; they operate on two specific sequences known as attachment sites. The integrase precisely recombines the attP site in the circular prophage genome with the attB site in the bacterial chromosome, resulting in stable lysogeny of the bacterium.Subjects--Topical Terms:

1017730
Biology, Genetics.

Phage integrases for gene therapy: From concept to application.
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245 1 0 $a Phage integrases for gene therapy: From concept to application.
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500 $a Source: Dissertation Abstracts International, Volume: 64-05, Section: B, page: 2012.
500 $a Adviser: Michele P. Calos.
502 $a Thesis (Ph.D.)--Stanford University, 2003.
520 $a Long term correction of many genetic disorders requires the gene therapy vector to become integrated into the recipient chromosome. This allows for reliable transmission of the introduced genes as the cell divides throughout the lifetime of the patient. Current solutions take advantage of the natural machinery of viruses to integrate the therapeutic gene into the recipient chromosome. While this strategy has proven effective in many cases, the use of viruses on human patients poses serious safety concerns. The integrating viruses most commonly used for gene therapy (retroviruses and lentiviruses) insert their genomes into the chromosome in a random fashion, without regard for the importance of the target site. This type of insertion has the potential of causing deleterious mutations, and has recently been documented as the cause of two leukemias in a gene therapy clinical trial. Here, I document the development of a novel system utilizing prokaryotic phage integrases that allows for site-specific integration of the gene therapy vector into safe places in patient genome. In nature, bacteriophage integrases catalyze the integration of the prophage genome into the chromosome of the host bacterium. Their function is distinct from that of retroviral integrases; they operate on two specific sequences known as attachment sites. The integrase precisely recombines the attP site in the circular prophage genome with the attB site in the bacterial chromosome, resulting in stable lysogeny of the bacterium.
520 $a As part of this work, I demonstrated that the &phis;C31 integrase functions efficiently in the mammalian cell environment, and also determined the minimum functional sizes of the attB and attP sites. I also showed that the human and mouse genomes contain native sequences termed “pseudo-attP” sites that resemble the wildtype attP site and can support integrase mediated site-specific recombination. Using a model gene therapy system in mice, I employed the &phis;C31 integrase system to achieve long term expression of a transgene at levels that were not previously possible. The &phis;C31 integrase has proven to be an extremely valuable and useful tool for gene therapy, and is currently being applied to real world clinical situations.
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