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Altered recombinases for genome modification ("Shuffled" recombinases)


Stanford Reference:

00-003


Abstract


The PhiC31 altered integrase technology potentially allows one to site-specifically integrate DNA into chromosomes with efficiency into predictable genomic sequences. Typically, the wild-type integrase facilitates site-specific integration in a way that reduces gene silencing effects. Because of the system’s simplicity, it can be carried out with conventional plasmid DNA, which may eliminate the need for viral vectors. This Marketing Summary highlights the system’s utility and distinguishes its features from other commercial genome editing technologies that are currently on the market.

The system can be used potentially in a wide range of cells including stem cells, primary cells, and numerous cell lines spanning mammalian and insect species. Moreover, the technology has potential uses for in vitro, in vivo, and ex vivo applications.

Specifically, the system is based on components from the PhiC31 phage that include an integrase and short sequences of DNA that provide the recombination sites for the integrase. The PhiC31 integrase is an enzyme that facilitates recombination between two short cis-acting DNA sequences called attachment, or att, sites. One sequence (known as the attB site) is carried on a vector bearing a nucleic acid of interest (e.g., a gene) and the other attachment site (known as the attP site) is in the genome of the cell. The enzyme can recognize native attP sites that are naturally part of a genome, or it can mediate recombination with an attP site engineered into a chromosome.

The term “altered” integrase means that the enzyme has been changed from its wild-type predecessor, thus endowing it with unique properties. Changes in the integrase potentially allow one to customize genomes by directing site-specific integration towards a given location in a genome. As part of the work done at Stanford, several altered integrases were produced that permit specific genetic engineering (see Sclimenti et al. publication noted below). Customizing an integrase may be achievable if one so chooses in order to meet a specialized need.

Customizable genome engineering technologies are not entirely new to the market. Examples include zinc finger nucleases (ZFNs), Transcription Activator-Like (TAL) Effector Nucleases and custom-made DNA-cutting enzymes using meganucleases. All of these approaches rely on the enzyme making a double-strand break to facilitate the genomic modification and could present some drawbacks such as lower frequency, a required higher dose, and background double-strand breaks / toxicity. Similarly, like these current marketed gene editing products, the technology may be used for interrupting gene expression.

The altered integrase technology may allow one to engineer a cell easily and with a predictable outcome: the gene of interest would go to known genomic locations, and, depending on location, may generate long-term robust gene expression that is not silenced as it often is from random integration.

The altered integrase technology is currently available for licensing in all fields of use.

Applications


  • Biologics production – the altered integrase system can be used to over-express genes from the genome for subsequent isolation and purification as well as rapidly generate isogenic clones that have a favorable expression profile
  • Drug discovery tool – useful in gene expression studies, screening and testing compounds against proteins, screening and testing translation modulators, and knock-out gene expression
  • Gene therapy – ex vivo and in vivo
  • Production of transgenics

Advantages


  • Easy and predictable engineering of tissues, stem cells, primary cell and cell lines
  • Unidirectional integration
  • Targets and binds to specific DNA sequence
  • No creation of double-strand breaks
  • More efficient and specific results

Publications



Additional information


More non-confidential information, including copies of the patents and patent applications, is available upon request. In addition to the issued patents noted below, an application is pending in Canada. The wild-type integrase technology (Stanford reference S97-168; US Patents 6,632,672, 7,361,641, and 8,227,249) is also available for licensing in certain areas.

Innovators & Portfolio



Patent Status



Date Released

 1/25/2013
 

Licensing Contact


Ximena Ares, Licensing Associate
650-724-0960 (Direct)
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Related Keywords


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S00-003 Altered recombinases for genome modification ("Shuffled" recombinases)