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Autism Speaks, SAGE Labs collaborate on plan to develop knockout rat models targeted toward treating autism

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BOULDER, Colo.—Autism advocacy group Autism Speaks and Sigma Life Science's Sigma Advanced Genetic Engineering Labs (SAGE) division have joined hands to develop genetically altered knockout rat models designed to mimic the symptoms of autism, a growing syndrome with mystery still shrouding its origins and diverse symptoms. A major goal of this partnership is aimed at driving forward basic research into the biological mechanisms of autism and related disorders, Fragile X and Rett syndrome.

Autism Speaks was founded in February 2005 by Bob and Suzanne Wright, who are grandparents of a child with autism. The autism science and advocacy organization is dedicated to funding research into the causes, prevention, treatments and a cure for autism; increasing awareness of autism spectrum disorders; and advocating for the needs of individuals with autism and their families.

Dr. Sophia Colamarino, vice president of research for Autism Speaks, says the organization partnered with SAGE to "further our ability to carry out translational research in autism. More model systems are sorely needed."

Combining Autism Speaks' specialized knowledge and autism research contacts combined with SAGE's technology will result in faster testing and adoption of the new models, Colamarino says.

Edward Weinstein, director of SAGE Labs, anticipates a strong response from the preclinical research sector when the new strains become commercially available next year.

"For studies of behavior, learning and cognition, the rat is the animal of choice due to its complex behavioral repertoire," Weinstein says. "With these new genetically modified rats, the richness of previous behavioral and physiological research can be leveraged and applied directly to autism. These new rat models will be validated in the laboratories of several scientists who will be studying brain development and behavior of the animals.

"Working in partnership with Autism Speaks, the leading organization in science, awareness and advocacy of autism-related issues, will provide the ideal opportunity to create a platform of very useful animal models for the research community," Weinstein adds. "This exciting development should be hugely beneficial to researchers seeking to improve the lives of people with autism."

The key to developing these new rat models is SAGE's Zinc Finger Nuclease (ZFN) technology, which allows SAGE to create knockout rats without the use of embryonic stem cells.

Until recently, it has been impossible to create knockout rat models in which targeted genes have been deactivated, Weinstein says. Using Sigma's CompoZr ZFN technology, part of its SAGEspeed model creation process, scientists now have the ability to produce knockout models designed specifically to mimic the symptoms of autism by targeting genes thought to be implicated in the disorder.

"We can then inject that ZFN into a one-cell rat embryo, where it will bind the targeted gene and cause a break in the DNA," Weinstein says. "This effectively 'knocks out,' or inactivates, the gene."

The one-cell embryo is then transferred into a surrogate rat, and 21 days later, a genetically modified rat is born and is exactly like every other rat, with the exception of the inactivation of that one specific gene that was targeted, he says.

"The challenge is in the validation of the models," Weinstein says. "SAGE will be testing these rats to see if there really are behavioral differences in them. That will be key to determining their usefulness."

The research community gets "kind of hung-up" on the term "genetic model," Weinstein says.

"Using the genetically modified rats, we can time exposures both in utero and during early post-natal life," he says. "Gene-environment interactions are extremely important to understand, and we hope that researchers will seek answers to those questions with these new autism model rats."

Dr. Geraldine Dawson, chief science officer of Autism Speaks, tells ddn, "This is the first time we have partnered with industry to assist in the validation of an animal model for autism. We chose to work with Sage Labs since it is uniquely positioned to develop a rat model of autism and related developmental disorders."

Autism Speaks "is not interested in any possible commercial opportunity in this venture," she says. Rather, she explains, "we are collaborating for the sole purpose of accelerating our discovery of drugs that can help reduce the challenging symptoms of autism."
"Our hope is that work with these new animal models will ultimately lead to the discovery of new drugs that can improve the lives of persons with autism or to new methods for diagnosis," Dawson says.

Weinstein says that although hampered by a number of factors—including an uncertain genetic basis and inadequate animal model systems—"autism is definitely a treatable disorder—anything is—if there is sufficient funding and resources. SAGE Labs simply hopes to make our contribution to the process by providing quality reagents."

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