Going to the rats

A scientific breakthrough by Sigma Advanced Genetic Engineering (SAGE) Labs enables creation of more sophisticated models of human disease

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ST. LOUIS—Sigma Life Science, the biological products and services business of Sigma-Aldrich, announced recently that its SAGE Labs initiative has successfully used its proprietary CompoZr Zinc Finger Nuclease (ZFN) technology to generate "knock-in" rats in which foreign genes have been inserted into the rat genome in a precisely targeted manner. 

This breakthrough achievement represents a major step forward in the creation of a transgenic animal, which may serve as more predictive models of human disease.

In a proof-of-concept study conducted by researchers at Sigma Advanced Genetic Engineering (SAGE) Labs, a copy of green fluorescent protein (GFP) was inserted in a targeted fashion into the Mdr1a gene of a rat, thus creating a rat that glows under special lighting conditions.  

The study, which has recently been accepted for publication, opens the doors to a variety of new applications including the tagging of genes with reporters such as GFP to measure gene expression patterns and replacement of rat genes with humanized versions.

According to Phil Simmons, marketing and business development manager at SAGE Labs, as a model organism, "the rat has been a gold standard in modeling human diseases for over the past century due to the fact that it is a relatively large animal (hence more intricate studies can be done on it), has higher cognitive and behavioral abilities, and is more representative of a human being in the way that it metabolizes drugs."

"Unfortunately, it wasn't until 2009 that a technology became available that could be used to engineer the rat genome is a very precise manner," he says. "Now that we have tools in place to engineer the rat genome, we can start making more predictive models that mimic human diseases more effectively. These models will be used to test the efficacy and safety of new game-changing drugs."

Although rats have long been the model organism of choice for disease research, scientists have been forced to use mouse models for over a quarter of a century, due to their amenability to genetic manipulation.

Simmons explains that the creation of rats with gene deletions, commonly called 'knock-outs,' using ZFN technology was first published in Science in 2009, and the ability to create rats with new genes introduced in their genome represents a leap forward in ZFN technology, allowing sophisticated genetic engineering of higher-level organisms and providing scientists with a choice of model organisms that can be used to investigate different diseases.

According to Simmons, major disease areas in which the rat should show improved predictivity over current mouse models include ADME/Tox, schizophrenia, Parkinson's disease, Alzheimer's disease, pain, depression, autism, xenograft studies and inflammation/immunology studies.

According to the company, Sigma Life Science's CompoZr ZFN technology is the only technique that has repeatedly been shown to make highly targeted mutations, and this breakthrough from SAGE Labs puts ZFN technology on par with classic ES cell-based gene targeting techniques in terms of application flexibility. SAGE Labs will use this technology, combined with its SAGEspeed model creation process, to produce a number of off-the-shelf rat models for use in the study of human diseases, as well as custom models for customers.

The project has been on the fast track since its introduction in Science 18 months ago, Simmons notes, saying, "The immediate next question was could you use the same technology that was used to make the knockout rat [CompoZr ZFN technology] and use it to insert something into the rat genome in a very targeted manner. SAGE scientists, led by Dr. Xiaoxia Cui, started working in the summer of 2009 on the Rat Knock-in Project, so it has been roughly one year."

Simmons also points out that the use of various transgenic technologies "give us as scientists a tool box in order to make animal models that more effectively model human disease."  

"A great example is a model we are working on for schizophrenia called the DISC1 Knockout Rat," he explains. "In human populations, it was observed that a large schizophrenic population in Scotland was lacking correct functioning of the DISC gene.  With this knowledge in hand, we deleted the DISC1 gene from the rat genome.  It is expected that the rats will display aspects of schizophrenia, and thus will serve as great testing grounds for new schizophrenia treatments."

"We have invested time and resources in developing the CompoZr and SAGEspeed platforms to help realize the enormous potential of this technology, enabling precise manipulation of the genome of living organisms," notes Dr. Edward Weinstein, director of SAGE Labs at Sigma Life Science. "This exciting advance is another example of how Sigma Life Science is pushing the limits of technology, establishing what we believe will become the new standard for the creation of genetically engineered research animals."

Going forward, Simmons notes that a whole new crop of applications is possible:
  • Create rat models with point mutations. These rats could be used to model diseases in which very small changes are made to the genome.
  • Tag genes with "reporter" proteins. Models can now be created in which genes are 'tagged' by fluorescent reporter genes. These models could be used as an assay to determine when specific genes are turned off or on.
  • Humanization of rat genes. Models can now be made in which rat genes are "swapped" for their human counterparts.  
"Imagine a rat that carries all of the proper genes for human drug metabolism," Simmons says. "This rat would be used to test the safety of drugs and would be much more predictive than what is available today."

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