Genetically engineered mice became a preferred animal model because, until very recently, they have been the only mammalian species where targeted genetic manipulations were possible, according to Kevin Gamber, Ph.D., product manager, Sigma Advanced Genetic Engineering (SAGE) Labs, Sigma-Aldrich.
But the rat remains the preferred species for neuroscience, cardiovascular, and toxicology research applications, among others, adds Dr. Gamber.
“Moreover, the anatomy, physiology, and social behavior of rat is closer to human than the mouse is, and we are seeing phenotypes modeling human disease in rat models that are not present in the equivalent mouse models,” he explains.
“The lack of rat knockouts has significantly hampered development of therapeutics.”
SAGE Labs reportedly opened new opportunities for drug development by creating rat knockout (KO) models using zinc finger nucleases (ZFNs). ZFNs recognize and cut specific DNA sequences and can be used on fertilized oocytes, opening the door to genetic manipulations in species other than mouse.
The introduced genetic change is hereditary and can be stably maintained by inbreeding. SAGE Labs produces a variety of rat KO lines covering a range from oncology to neurosciences to cardiovascular disease.
In collaboration with the Michael J. Fox Foundation, SAGE Labs designed several rat models lacking genes associated with Parkinson’s disease. The pathological hallmark of the disease is loss of dopamine neurons, a phenotype that so far has been difficult to reproduce in mouse models. In the absence of neurodegeneration, mouse models cannot be used to test novel neuroprotective agents.
“Two of our rat KO models show a progressive neurodegenerative phenotype,” continues Dr. Gamber. “Hind limb deficits occur at about five months of age and progress rapidly. More subtle motor deficits occur even earlier. The preliminary tissue analysis indicates significant loss of dopaminergic neurons.”
Highly developed social behavior in rats can be used to model diseases such as autism and Fragile X. SAGE Labs designed six KO rat models using genes linked to certain components of autism spectrum disorders. Disruption of the FMR1 gene, the primary cause of Fragile X syndrome, indeed results in curtailing of rats social play, a behavior that cannot be assessed in mouse.
In collaboration with Autism Speaks, SAGE Labs continues to design rat models for measuring neuronal signaling and its effect on social interactions.
“Genetically engineered rats complement mouse in many research areas, especially where translation of mouse to human has shown to be inadequate,” says Dr. Gamber.
“We will continue expanding our platform by providing comprehensive phenotyping capabilities to our genetically engineered rat models.”